Instructions for use ‘Template Research Protocol’
Observational study of pediatric thrombotic disease: the Throm-PED registry1214755508000Scientific Subcommittee Pediatric and Neonatal Hemostasis and Thrombosisof the International Society of Thrombosis and HaemostasisPROTOCOL TITLE ‘Observational study of pediatric thrombotic disease: the Throm-PED registry’Protocol IDThrom-PED 2018Short titleThrom-PED registryVersion1Date19-06-2018Coordinating investigator/project leaderOn behalf of IPTNDr CH van Ommen, chair steering committee IPTNPrincipal investigator(s) All PIs of participating sites (Appendix 1)For our center:………….Sponsor Scientific Subcommittee (SSC) Pediatric and Neonatal Hemostasis and Thrombosisof the International Society of Thrombosis and Haemostasis (ISTH)Subsidising partyNoneIndependent expert (s)For our center?:…..PROTOCOL SIGNATURE SHEETNameSignatureDateSponsor or legal representative:…………..Head of Department:…………………..[Coordinating Investigator/Project leader/Principal Investigator]:Steering committee IPTNChair Dr CH van OmmenTABLE OF CONTENTS TOC \o "1-3" \u 1.INTRODUCTION AND RATIONALE PAGEREF _Toc513982990 \h 101.1General background thromboembolic disease in children PAGEREF _Toc513982991 \h 101.2Research in pediatric patients with specific thrombotic events PAGEREF _Toc513982995 \h 111.3The use, effectiveness and safety of antithrombotic agents PAGEREF _Toc513982996 \h 111.4The International Pediatric Thrombosis Network PAGEREF _Toc513982997 \h 121.5Rationale PAGEREF _Toc513982998 \h 132.OBJECTIVES PAGEREF _Toc513983001 \h 133.STUDY DESIGN PAGEREF _Toc513983002 \h 134.STUDY POPULATION PAGEREF _Toc513983004 \h 144.1Population (base) PAGEREF _Toc513983005 \h 144.2Inclusion criteria PAGEREF _Toc513983006 \h 144.3Exclusion criteria PAGEREF _Toc513983007 \h 145.TREATMENT OF SUBJECTS PAGEREF _Toc513983010 \h 146.INVESTIGATIONAL PRODUCT PAGEREF _Toc513983011 \h 147.NON-INVESTIGATIONAL PRODUCT PAGEREF _Toc513983012 \h 148.METHODS PAGEREF _Toc513983013 \h 148.1Main study parameters/endpoints PAGEREF _Toc513983014 \h 148.2Secondary study parameters/outcomes PAGEREF _Toc513983015 \h 158.3Study procedures PAGEREF _Toc513983016 \h 168.3.1Recruitment PAGEREF _Toc513983017 \h 168.3.2Data collection PAGEREF _Toc513983018 \h 168.4Withdrawal of individual subjects PAGEREF _Toc513983019 \h 178.5Replacement of individual subjects after withdrawal PAGEREF _Toc513983020 \h 178.6Follow-up of subjects withdrawn from treatment PAGEREF _Toc513983021 \h 178.7Premature termination of the study PAGEREF _Toc513983022 \h 179.SAFETY REPORTING PAGEREF _Toc513983023 \h 179.1Temporary halt for reasons of subject safety PAGEREF _Toc513983024 \h 179.2AEs, SAEs PAGEREF _Toc513983025 \h 189.3Annual safety report PAGEREF _Toc513983026 \h 189.4Follow-up of adverse events PAGEREF _Toc513983027 \h 1810.STATISTICAL ANALYSIS PAGEREF _Toc513983028 \h 1810.1Selection of subjects for analysis PAGEREF _Toc513983029 \h 1810.2Analysis PAGEREF _Toc513983030 \h 1911.ETHICAL CONSIDERATIONS PAGEREF _Toc513983031 \h 1911.1Regulation statement PAGEREF _Toc513983032 \h 1911.2Recruitment and consent PAGEREF _Toc513983033 \h 1911.3Objection by minors or incapacitated subjects (if applicable) PAGEREF _Toc513983034 \h 1911.4Benefits and risks assessment, group relatedness PAGEREF _Toc513983035 \h 2011.5Compensation for injury PAGEREF _Toc513983036 \h 2011.6Incentives (if applicable) PAGEREF _Toc513983037 \h 2012.ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION PAGEREF _Toc513983041 \h 2012.1Handling and storage of data and documents PAGEREF _Toc513983042 \h 2012.2Monitoring and Quality Assurance PAGEREF _Toc513983043 \h 2112.3Amendments PAGEREF _Toc513983044 \h 2112.4Annual progress report PAGEREF _Toc513983045 \h 2112.5Temporary halt and (prematurely) end of study report PAGEREF _Toc513983046 \h 2112.6Public disclosure and publication policy PAGEREF _Toc513983047 \h 2113.REFERENCES PAGEREF _Toc513983048 \h 22LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS ABRABR form, General Assessment and Registration form, is the application form that is required for submission to the accredited Ethics Committee (In Dutch, ABR = Algemene Beoordeling en Registratie)AEAdverse EventALLAcute Lymphoblastic LeukemiaCACompetent AuthorityCCMOCentral Committee on Research Involving Human Subjects; in Dutch: Centrale Commissie Mensgebonden OnderzoekCRNMClinically relevant non majorCVCurriculum VitaeDOACDirect Oral AntiCoagulantDSMBData Safety Monitoring BoardEUEuropean UnionGCPGood Clinical PracticeICInformed ConsentIMPInvestigational Medicinal Product IPTNInternational Pediatric Thrombosis NetworkISTHInternational Society of Thrombosis and HaemostasisLMWHLow-molecular-weight heparinMETC Medical research ethics committee (MREC); in Dutch: medisch ethische toetsing commissie (METC)RCTRandomized controlled trial(S)AE(Serious) Adverse Event SponsorThe sponsor is the party that commissions the organisation or performance of the research, for example a pharmaceuticalcompany, academic hospital, scientific organisation or investigator. A party that provides funding for a study but does not commission it is not regarded as the sponsor, but referred to as a subsidising party.SSCScientific SubCommitteeSVTSinovenous thrombosisTEThromboembolic event VKAVitamin K antagonistVTEVenous thromboembolic eventWbpPersonal Data Protection Act (in Dutch: Wet Bescherming Persoonsgevens)WMOMedical Research Involving Human Subjects Act (in Dutch: Wet Medisch-wetenschappelijk Onderzoek met MensenSUMMARYRationale: Thromboembolic events (TEs) are increasingly recognized in children, but the incidence remains low compared to adults. Due to the low rate of TE in children in general and those various types of TE in particular, large clinical trials regarding epidemiology, risk factors, diagnosis and treatment of these various types of TE are lacking and difficult to execute in both neonates and children. Most of the recommendations of current guidelines for the general treatment of pediatric TE are extrapolated from adult studies despite several differences between TE in adults and children. It is important to increase knowledge about pediatric thrombosis to improve care in this age group. Therefore, this registry is needed. Objective: The primary objectives include: 1) prospective collection of essential, basic data from all children with TE, 2) evaluation of the epidemiology, risk factors, diagnosis, treatment and outcome of specific TEs and 3) investigation of the safety and efficacy of all used therapeutic agents in (preterm) neonates, children and adolescents with various types of thromboembolic disease. The secondary objectives include: 1) documentation of treatment patterns and clinical course of all TEs over time and 2) evaluation of clinical outcomes associated with the use of therapeutic agents in (preterm) neonates, children and adolescents with various types of thromboembolic disease.Study design: International, multicentre, prospective observational cohort registry studyStudy population: (Preterm) neonates, infants, children and adolescents (0-18 years old) with thromboembolic diseaseMain study parameters/endpoints: 1) The incidence, the distribution of age, gender, TE type, location, the number and types of risk factors, the presentation and the frequency of various treatment options of all TEs in children, 2) the incidence, the distribution of age and gender, the number and types of risk factors, the presentation, the frequency of various treatment options, and the frequency and severity of short-and long-term outcomes of specific TEs in children (depending on the type of TE), 3) efficacy outcomes may include frequency of recurrent TE, death as result of TE, no change or extension of thrombotic burden and safety outcomes may include major bleeding and clinically relevant non major (CRNM) bleeding, depending on the research question of the project. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: This is a observational study without any additional blood samples, questionnaires, site visits etc. So the burden is minimal for the included patients. INTRODUCTION AND RATIONALEGeneral background thromboembolic disease in children Thromboembolic events (TEs) are increasingly recognized in children, but the incidence remains low compared to adults. Annual incidences of venous thromboembolism (VTE) in the general pediatric population range from 0.14 to 0.21 per 10,000 children.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UdWNrdXZpZW5lPC9BdXRob3I+PFllYXI+MjAxMTwvWWVh
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ADDIN EN.CITE.DATA (3) The incidence of arterial thrombosis in children is much lower than that of VTE. The lower frequency of TEs compared to adults may be explained by decreased exposure to acquired prothrombotic risk factors such as hormone therapy, pregnancy and puerperium, and malignancy, the enhanced capacity to inhibit thrombin throughout childhood due to increased plasma concentrations of the thrombin inhibitor alpha-2-macroglobulin, and the decreased frequency of diseases associated with vascular damage such as diabetes, dyslipidemias and hypertension. ADDIN EN.CITE <EndNote><Cite><Author>Mitchell</Author><Year>1991</Year><RecNum>18</RecNum><DisplayText>(4)</DisplayText><record><rec-number>18</rec-number><foreign-keys><key app="EN" db-id="dt5z52azvxd52qesvxkx0pv4dvzff0tzpeas" timestamp="1441791134">18</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mitchell,L.</author><author>Piovella,F.</author><author>Ofosu,F.</author><author>Andrew,M.</author></authors></contributors><auth-address>Department of Pediatrics, McMaster University Health Sciences Centre, Chedoke-McMaster Hospitals, Hamilton, Ontario, Canada</auth-address><titles><title>Alpha-2-macroglobulin may provide protection from thromboembolic events in antithrombin III-deficient children</title><secondary-title>Blood</secondary-title></titles><periodical><full-title>Blood</full-title></periodical><pages>2299-2304</pages><volume>78</volume><number>9</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>Adolescence</keyword><keyword>Adult</keyword><keyword>Antithrombin III</keyword><keyword>deficiency</keyword><keyword>Child</keyword><keyword>Child,Preschool</keyword><keyword>Heparin</keyword><keyword>pharmacology</keyword><keyword>Human</keyword><keyword>Support,Non-U.'t</keyword><keyword>Thrombin</keyword><keyword>antagonists & inhibitors</keyword><keyword>metabolism</keyword><keyword>Thromboembolism</keyword><keyword>prevention & control</keyword><keyword>alpha-Macroglobulins</keyword><keyword>physiology</keyword><keyword>Thrombosis</keyword><keyword>complications</keyword><keyword>Heparin Cofactor II</keyword><keyword>Ontario</keyword><keyword>Canada</keyword></keywords><dates><year>1991</year><pub-dates><date>11/1/1991</date></pub-dates></dates><label>20</label><urls></urls></record></Cite></EndNote>(4) In general, VTE is typically diagnosed in hospitalized children, especially critically ill neonates with catheters and adolescents with a combination of risk factors.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gT21tZW48L0F1dGhvcj48WWVhcj4yMDAxPC9ZZWFy
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ADDIN EN.CITE.DATA (6) Pediatric VTE is usually located in the venous system draining the lower and upper limbs. In contrast to adults, deep vein thrombosis occurs predominantly in the upper venous system due to the insertion of central venous catheters. ADDIN EN.CITE <EndNote><Cite><Author>Andrew</Author><Year>1994</Year><RecNum>23</RecNum><DisplayText>(7)</DisplayText><record><rec-number>23</rec-number><foreign-keys><key app="EN" db-id="dt5z52azvxd52qesvxkx0pv4dvzff0tzpeas" timestamp="1441791134">23</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Andrew,M.</author><author>David,M.</author><author>Adams,M.</author><author>Ali,K.</author><author>Anderson,R.</author><author>Barnard,D.</author><author>Bernstein,M.</author><author>Brisson,L.</author><author>Cairney,B.</author><author>DeSai,D.</author></authors></contributors><auth-address>Children's Hospital at Chedoke-McMaster, Hamilton, Ontario, Canada</auth-address><titles><title>Venous thromboembolic complications (VTE) in children: first analyses of the Canadian Registry of VTE</title><secondary-title>Blood</secondary-title></titles><periodical><full-title>Blood</full-title></periodical><pages>1251-1257</pages><volume>83</volume><number>5</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>Administration,Oral</keyword><keyword>Anticoagulants</keyword><keyword>administration & dosage</keyword><keyword>Child,Preschool</keyword><keyword>Female</keyword><keyword>Human</keyword><keyword>Infant</keyword><keyword>Male</keyword><keyword>Ontario</keyword><keyword>Pulmonary Embolism</keyword><keyword>epidemiology</keyword><keyword>therapy</keyword><keyword>Recurrence</keyword><keyword>Support,Non-U.'t</keyword><keyword>Thromboembolism</keyword><keyword>Thrombophlebitis</keyword><keyword>complications</keyword><keyword>Registries</keyword><keyword>Thrombosis</keyword><keyword>Incidence</keyword><keyword>mortality</keyword><keyword>Canada</keyword><keyword>Heparin</keyword><keyword>Adult</keyword></keywords><dates><year>1994</year><pub-dates><date>3/1/1994</date></pub-dates></dates><label>25</label><urls></urls></record></Cite></EndNote>(7) In addition, VTE also occurs in the central nervous system (CNS) and in vessels associated with specific organs.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CcmFuZGFvPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48
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ADDIN EN.CITE.DATA (13) These age-dependent differences include variances in volume of distribution, binding and clearance of the drugs as well as variances in hemostatic proteins, which differ both qualitatively and quantitatively in neonates and young infants from those in older children and adults. ADDIN EN.CITE <EndNote><Cite><Author>Andrew</Author><Year>1992</Year><RecNum>14</RecNum><DisplayText>(14)</DisplayText><record><rec-number>14</rec-number><foreign-keys><key app="EN" db-id="dt5z52azvxd52qesvxkx0pv4dvzff0tzpeas" timestamp="1441791134">14</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Andrew,M.</author><author>Vegh,P.</author><author>Johnston,M.</author><author>Bowker,J.</author><author>Ofosu,F.</author><author>Mitchell,L.</author></authors></contributors><auth-address>Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada</auth-address><titles><title>Maturation of the hemostatic system during childhood</title><secondary-title>Blood</secondary-title></titles><periodical><full-title>Blood</full-title></periodical><pages>1998-2005</pages><volume>80</volume><number>8</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>Adolescence</keyword><keyword>Aging</keyword><keyword>physiology</keyword><keyword>Blood Coagulation Factors</keyword><keyword>analysis</keyword><keyword>antagonists & inhibitors</keyword><keyword>Child</keyword><keyword>Child,Preschool</keyword><keyword>Comparative Study</keyword><keyword>Fibrinolysis</keyword><keyword>Hemostasis</keyword><keyword>Human</keyword><keyword>Infant</keyword><keyword>Reference Values</keyword><keyword>Support,Non-U.'t</keyword><keyword>Vitamin K</keyword><keyword>pharmacology</keyword><keyword>Adult</keyword><keyword>Cohort Studies</keyword><keyword>blood</keyword><keyword>Heparin</keyword><keyword>Ontario</keyword><keyword>Canada</keyword></keywords><dates><year>1992</year><pub-dates><date>10/15/1992</date></pub-dates></dates><label>16</label><urls></urls></record></Cite></EndNote>(14)Current antithrombotic treatment of VTE consists of initial low-molecular-weight heparin (LMWH) followed by LMWH or vitamin K antagonists (VKA) for a total duration of 3 to 6 months. Thrombolytic agents are reserved for life-threatening thromboembolic disease. In some patients alternative anticoagulants, such as argatroban, bivalirudin and fondaparinux are used. ADDIN EN.CITE <EndNote><Cite><Author>Young</Author><Year>2017</Year><RecNum>159</RecNum><DisplayText>(15)</DisplayText><record><rec-number>159</rec-number><foreign-keys><key app="EN" db-id="rzp05x5dfvpzwqeddatv2feivafet0pvvf9x" timestamp="1525081068">159</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Young, G.</author><author>Male, C.</author><author>van Ommen, C. H.</author></authors></contributors><auth-address>Children's Hospital Los Angeles, University of Southern California Keck School of Medicine. Electronic address: gyoung@chla.usc.edu.
Department of Paediatrics, Medical University of Vienna, Vienna, Austria.
Department of Pediatric Hematology/Oncology, Erasmus MC Sophia's Children's Hospital, Rotterdam, Netherlands.</auth-address><titles><title>Anticoagulation in children: Making the most of little patients and little evidence</title><secondary-title>Blood Cells Mol Dis</secondary-title></titles><periodical><full-title>Blood Cells Mol Dis</full-title></periodical><pages>48-53</pages><volume>67</volume><edition>2017/05/30</edition><dates><year>2017</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>1096-0961 (Electronic)
1079-9796 (Linking)</isbn><accession-num>28552476</accession-num><urls><related-urls><url>(16)30246-7 [pii]
10.1016/j.bcmd.2017.05.003</electronic-resource-num><language>eng</language></record></Cite></EndNote>(15) Treatment of arterial TE depends on the location of thrombosis and may consist of platelet aggregation inhibitors or anticoagulation agents.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb25hZ2xlPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48
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ADDIN EN.CITE.DATA (23-25) As a consequence, the level of evidence of available pediatric guidelines remained low since the first national registration of VTE in Canada of Maureen Andrew. ADDIN EN.CITE <EndNote><Cite><Author>Andrew</Author><Year>1994</Year><RecNum>23</RecNum><DisplayText>(7)</DisplayText><record><rec-number>23</rec-number><foreign-keys><key app="EN" db-id="dt5z52azvxd52qesvxkx0pv4dvzff0tzpeas" timestamp="1441791134">23</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Andrew,M.</author><author>David,M.</author><author>Adams,M.</author><author>Ali,K.</author><author>Anderson,R.</author><author>Barnard,D.</author><author>Bernstein,M.</author><author>Brisson,L.</author><author>Cairney,B.</author><author>DeSai,D.</author></authors></contributors><auth-address>Children's Hospital at Chedoke-McMaster, Hamilton, Ontario, Canada</auth-address><titles><title>Venous thromboembolic complications (VTE) in children: first analyses of the Canadian Registry of VTE</title><secondary-title>Blood</secondary-title></titles><periodical><full-title>Blood</full-title></periodical><pages>1251-1257</pages><volume>83</volume><number>5</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>Administration,Oral</keyword><keyword>Anticoagulants</keyword><keyword>administration & dosage</keyword><keyword>Child,Preschool</keyword><keyword>Female</keyword><keyword>Human</keyword><keyword>Infant</keyword><keyword>Male</keyword><keyword>Ontario</keyword><keyword>Pulmonary Embolism</keyword><keyword>epidemiology</keyword><keyword>therapy</keyword><keyword>Recurrence</keyword><keyword>Support,Non-U.'t</keyword><keyword>Thromboembolism</keyword><keyword>Thrombophlebitis</keyword><keyword>complications</keyword><keyword>Registries</keyword><keyword>Thrombosis</keyword><keyword>Incidence</keyword><keyword>mortality</keyword><keyword>Canada</keyword><keyword>Heparin</keyword><keyword>Adult</keyword></keywords><dates><year>1994</year><pub-dates><date>3/1/1994</date></pub-dates></dates><label>25</label><urls></urls></record></Cite></EndNote>(7) At the moment large international RCTs are being performed by pharmaceutical companies, comparing direct oral anticoagulants (DOACs) to standard of care, which will provide pharmacokinetic, pharmacodynamic and safety data of these new drugs in selected population of children with thrombosis.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYWx0b248L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (26) Research in pediatric patients with specific thrombotic eventsDespite the current DOAC studies, many questions remain, which will not be answered in those new drugs trials such as the natural history of arterial and venous thrombosis in (preterm) neonates and children, optimal diagnostics and effective and safe treatment of specific TEs such as pulmonary embolism, neonatal renal vein thrombosis, arterial TE and of TEs in specific diseases. The incidences of those TEs are so low that international, multicenter, prospective observational studies are needed to gather information about epidemiology, risk factors, diagnosis, treatment and outcome in order to improve management. Through the long-term systematic follow-up of pediatric patients with these specific TEs, the Throm-PED registry will contribute to the optimization of care of these patients. The use, effectiveness and safety of antithrombotic agentsIn future, there will be several antithrombotic agents available for treatment of pediatric TEs: conventional agents such as unfractionated heparin, LMWH and VKAs, alternative anticoagulants including argatroban, bivalirudin and fondaparinux, and new anticoagulants, such as DOACs. It is anticipated that more will become available in the future. Not all antithrombotic drugs will be available in all countries worldwide. And as evidence is lacking, physician’s preferences may cause various treatment regimens among countries or even among centers in one country. By collecting patient data, including used antithrombotic agents, the Throm-PED registry can report and follow changes in current medication use patterns worldwide.As mentioned above, most of the antithrombotic drugs have not been studied in randomized trials, and most RCTs on new drugs, such as DOACs are safety and no efficacy trials. As a consequence, there remains much to be learned about the short- and long-term outcomes associated with all antithrombotic agents. The Throm-PED registry will collect data on baseline disease characteristics, risk factors, used antithrombotic agents and clinical outcome and thereby enabling estimation of effectiveness of the antithrombotic drugs in various thrombotic events in various patient groups.Furthermore, in addition to the traditional post-marketing registries of new antithrombotic agents, the registry may help to study safety of these drugs in “real life”. The registry enables adequate sample sizes and unselective inclusion of all patients with and without severe underlying diseases, thus allowing worldwide investigation of the true risks and benefits of antithrombotic therapy. The International Pediatric Thrombosis NetworkThe Throm-PED registry is an initiative of the International Pediatric Thrombosis Network (IPTN), which has been initiated at the Scientific Subcommittee (SCC) on Pediatric/Neonatal Hemostasis and Thrombosis meeting in Berlin (ISTH congress, 2017), to empower international research collaboration. This Network consists of pediatric thrombosis expert centers across the world whose ultimate goal is to bring the best treatment to pediatric patients with thrombosis. The aims of the Network are Collaborative clinical research: to design and conduct epidemiological research, and develop an international trial network, to link academic and industry partners to initiate and conduct clinical trials, and to incorporate translational research into clinical trials;Promotion of good clinical practice: development of guidelines and consensus statements; promotion via educational tools, lectures and publications. Worldwide every center taking care of neonates and/or children with TE is allowed to participate in the IPTN and can include patients in the Throm-PED registry. This registry consists of a minimum dataset to register the essential data of all neonates and children with thrombosis and will be extended with additional datasets of future research projects.The database is a REDCap database provided by the ISTH.RationaleThe Throm-PED registry is established to increase knowledge about the epidemiology, risk factors, diagnosis, treatment and short- and long-term outcome of TE in general, but of specific TEs in particular, such as neonatal renal vein thrombosis, portal vein thrombosis, pulmonary embolism, catheter-related thrombosis and arterial thrombosis. Furthermore, a prospective disease-based registry will enable investigation of use, safety and efficacy of all antithrombotic agents in “real life”. (Preterm) neonates and children until 18 years of age will be included from all over the world. Patients will be followed prospectively as long as the patients are followed by their treating physician for TE or its complications. OBJECTIVESPrimary Objectives: 1. Prospectively collect essential, basic data from (preterm) neonates, children, and adolescents with TEs 2. Evaluate the epidemiology, risk factors, diagnosis, treatment and short- and long-term outcome of specific TEs in (preterm) neonates, children and adolescents 3. Evaluate the safety and efficacy of all used therapeutic agents in (preterm) neonates, children and adolescents with various types of TESecondary Objectives: 1. Document drug treatment patterns and clinical course of (preterm) neonates, children and adolescents with various types of TE over time. 2. Evaluate clinical outcomes associated with the use of therapeutic agents in (preterm) neonates, children and adolescents with various types of TESTUDY DESIGNThis is an international, multicenter, prospective observational cohort registry study of children with thromboembolic disease. All (preterm) neonates, children and adolescents with thromboembolic disease who are treated at a participating Throm-PED site will be considered for enrollment into the registry. Data will be collected longitudinally from the patient’s medical record or electronic health record. Patients will be followed prospectively as long as they are seen by their treating physician for TE or its complications. STUDY POPULATIONPopulation (base) (Preterm) neonates, infants, children and adolescents (0-18 years old) with thromboembolic disease are eligible for this prospective cohort study. Inclusion criteriaIn order to be eligible to participate in this study, a subject must meet all of the following criteria:1. Pediatric patients until 18 years of age with thromboembolic disease2. Subject (and/or parent/legal guardian when required) is able to provide written informed consent and willing to comply with study proceduresExclusion criteriaA potential subject who meets any of the following criteria will be excluded from participation in this study:Patients older than 18 years of age at the time of thromboembolic diseasePatients without written informed consentTREATMENT OF SUBJECTSThe included patients with TE will be treated according to the treating physician’s discretion.INVESTIGATIONAL PRODUCT Not applicableNON-INVESTIGATIONAL PRODUCTNot applicableMETHODSMain study parameters/endpointsThe incidence, the distribution of age, gender, TE type, location, the number and types of risk factors, the presentation and the frequency of various treatment options of all TEs in childrenThe incidence, the distribution of age and gender, the number and types of risk factors, the presentation, the frequency of various treatment options, and the frequency and severity of short-and long-term outcomes of specific TEs in children (depending on the type of TE)Efficacy outcomes may include frequency of recurrent TE, death as result of TE, no change or extension of thrombotic burden and safety outcomes may include major bleeding and clinically relevant non major (CRNM) bleeding, depending on the research question of the project. Bleeding definitions, are based on the definitions as defined by the Perinatal and Paediatric Haemostasis SSC of the ISTH. ADDIN EN.CITE <EndNote><Cite><Author>Mitchell</Author><Year>2011</Year><RecNum>189</RecNum><DisplayText>(27)</DisplayText><record><rec-number>189</rec-number><foreign-keys><key app="EN" db-id="2wzxxdaznpexadeweeupsw2ftw0sz0staptw" timestamp="1526211600">189</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mitchell, L. G.</author><author>Goldenberg, N. A.</author><author>Male, C.</author><author>Kenet, G.</author><author>Monagle, P.</author><author>Nowak-Gottl, U.</author><author>Perinatal,</author><author>Paediatric Haemostasis Subcommittee of the, S. S. C. of the Isth</author></authors></contributors><auth-address>Stollery Children's Hospital, Edmonton, AB, Canada. Lesley.Mitchell@albertahealthservices.ca</auth-address><titles><title>Definition of clinical efficacy and safety outcomes for clinical trials in deep venous thrombosis and pulmonary embolism in children</title><secondary-title>J Thromb Haemost</secondary-title></titles><periodical><full-title>J Thromb Haemost</full-title></periodical><pages>1856-8</pages><volume>9</volume><number>9</number><keywords><keyword>Child</keyword><keyword>Clinical Trials as Topic/*standards</keyword><keyword>Endpoint Determination/standards</keyword><keyword>Fibrinolytic Agents/pharmacology</keyword><keyword>Humans</keyword><keyword>Pulmonary Embolism/*drug therapy/prevention & control</keyword><keyword>Safety</keyword><keyword>Societies, Medical</keyword><keyword>Treatment Outcome</keyword><keyword>Venous Thrombosis/*drug therapy/prevention & control</keyword></keywords><dates><year>2011</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>1538-7836 (Electronic)
1538-7836 (Linking)</isbn><accession-num>21884565</accession-num><urls><related-urls><url>;(27) Major bleeding is defined as a composite (ie, any) of the following:Fatal bleedingClinically overt bleeding associated with a decrease in hemoglobin of at least 20 g/L (ie, 2 g/dL) in a 24-hour periodBleeding that is retroperitoneal, pulmonary, intracranial, or otherwise involves the central nervous systemCRNM bleeding is defined as either of the following:Overt bleeding for which blood product is administered and not directly attributable to the subject’s underlying medical conditionBleeding that requires medical or surgical or percutaneous intervention to restore hemostasis, other than in an operating suiteSecondary study parameters/outcomesthe frequency and types of various treatment options over time in various TEThe outcomes including efficacy and safety outcomes, but in addition specific outcomes associated with certain types of TE for example kidney function in renal vein thrombosis, and development of esophageal varices in portal vein thrombosisStudy proceduresRecruitmentPotential participants (and/or parents/legal guardians) who meet the inclusion criteria will be approached during a visit to the IPTN site. If the adolescent or minor child’s parent/legal guardian have read the patient information forms, got answers to all the questions, and agree to participate, then written informed consent will be obtained per each enrolling site’s institutional requirements. All enrolled patients and/or their parent/legal guardian will get a copy of the signed informed consent forms. Study participation will be written down in the patient’s medical record. Each participant will be assigned a unique study number. This study number will only be known to authorized staff of the study site of that particular study patient. Data collectionBaseline data will be collected directly from the participating patient when they visit the IPTN site and extracted from the patient’s medical record.All data will be collected in a web-based database, a REDCap database, which will be accessible on the website page of the IPTN on the website of the ISTH. (redcap.)Baseline Data collection may include:Contact email address of principal investigatorDemographic information: age, genderFamily history of thrombosisType of thrombosisPresentationDiagnostic methodsLocation of thrombosisRisk factors, such as thrombophilia, associated conditionsTreatment of thrombosisAfter enrollment, clinical evaluation will occur as standard of care prescribes, usually 1 to 4 times a year. Follow-up data will be collected directly from the participating patient when they visit the IPTN site and extracted from the patient’s medical record with the goal of entering data approximately every 6 to 12 months.Follow up data collection may include:Interval changes to Baseline DataCurrent and interval medication exposureReasons for changes in medication regimenComplications antithrombotic therapy including bleeding complicationsShort term outcomes including death, recurrent thrombosis, and thrombotic burdenLong term outcomes including post thrombotic syndrome and thrombotic burdenOutcome associated with specific locations of TE or disease, such as hypertension and kidney atrophy in renal vein thrombosis, or adjustment or cessation of anticancer therapy in cancer related thrombosis.Withdrawal of individual subjectsSubjects can leave the study at any time for any reason if they wish to do so without any consequences. The investigator can decide to withdraw a subject from the study for urgent medical reasons.Replacement of individual subjects after withdrawalNot applicableFollow-up of subjects withdrawn from treatmentNot applicable Premature termination of the studyNot applicableSAFETY REPORTINGTemporary halt for reasons of subject safetyIn accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the study if there is sufficient ground that continuation of the study will jeopardise subject health or safety. The sponsor will notify the accredited METC without undue delay of a temporary halt including the reason for such an action. The study will be suspended pending a further positive decision by the accredited METC. The investigator will take care that all subjects are kept informed. AEs, SAEs The Throm-PED registry is a prospective, observational study without additional laboratory, radiologic or other investigations. Therefore, reporting of (S)AEs to the medical ethical committee is not applicable. The antithrombotic drugs being observed are 1) lawfully marketed products not under investigational new drug regulations, 2) not investigational, 3) not under study in this protocol for a significant label change, 4) not under study in this protocol for a significant change in advertising, and 5) not under study in this protocol for a new route of administration or dosage level. If investigated in one of the projects, the investigator will report the efficacy and safety of these drugs to the Throm-PED registry via electronic data capture.Annual safety reportNot applicableFollow-up of adverse eventsNot applicableSTATISTICAL ANALYSISThis prospective observational registry will collect essential data about children with thrombotic disease who are included in the Throm-PED registry. Furthermore, data from the Throm-PED registry will be used for a variety of different projects. Each project will develop its own statistical plan based on proposed use. There is no maximum sample size; all eligible patients are candidates for inclusion in the Throm-PED registry and subsequent research projects.Selection of subjects for analysisEssential data from the Throm-PED Registry will be used to investigate the epidemiology, risk factors, diagnosis, treatment and follow-up of (specific) TEs in pediatric patients. In this instance, individual patients will be prospectively identified for future analyses at the time that they meet pre-specified inclusion criteria for the study (e.g., when they start the studied medication or when they develop a specific TE). Alternatively, studies may also be performed using a retrospective cohort design (i.e., patients and controls may be identified after data are collected but prior to data-analyses).AnalysisDescriptive statistics will be used to describe the Throm-PED registry and evaluate the demographic and clinical characteristics of included patients, type of thrombosis, risk factors for thrombosis, treatment, efficacy and safety of various anticoagulant and thrombolytic medication, and short-term and long-term follow-up, and regional differences. Other data analyses (e.g., medication utilization studies, identification of risk factors associatedwith clinical outcomes) will be performed as scientifically appropriate.Statistical modeling approaches will be determined by the specific study question, but will likely include Cox proportional hazard or Poisson regression modeling for cohort studies. Simple comparisons of incidence rates (e.g., rate ratios or standardized incidence ratios) may be appropriate for very rare outcomes.ETHICAL CONSIDERATIONSRegulation statementThis study will be conducted according to the principles of the Declaration of Helsinki (version 64, October 2013) and in accordance with the Medical Research Involving Human Subjects Act (WMO) and other guidelines, regulations and Acts.Recruitment and consentPatients with TE will be asked to participate. Informed consent will be asked by the investigator or treating physician. Decision consideration of one to two weeks will be given. Also, all participants must review, understand, agree to, and personally sign and date the informed consent form prior to enrolment in the study. If the subjects’ age is between 12-18 years, the custodial parents and/or legal guardians as well as the patient will need to provide informed consent. In case of subjects’ incompetence, the subject will not be asked to participate. Before signing the informed consent form, all participants will be given the chance to ask all their questions regarding the study and their possible participation. Informed consent forms will also be signed and dated by a medical doctor, or a Clinical Research Associate (CRA), authorised by the main investigator. The patient receives a copy of the informed consent form and the original form is filed by the investigator. Subjects are free to withdrawal from participating in this study at any time.Objection by minors or incapacitated subjects (if applicable)We will fully inform the child and the child’s custodial parent(s) or guardian both orally by the treating physician as well as in writing by the patient information letter (PIF). There is one PIF for the minor subject and one for the parents or caregivers. The informed consent form will state that when a minor objects to participation in the study, informed consent will be invalidated. The informed consent form will also state that the parents of a minor subject are able to withdraw their consent at any point during the project without explaining the reason. If a minor subject expresses an objection or wants to withdraw, the child’s participation will be discontinued.Benefits and risks assessment, group relatednessThis is a prospective observational study without additional blood samples, site visits, questionnaires etc. Therefore, the burden for the patient and parents or guardians will be minimal. Thromboembolic events (TEs) are increasingly recognized in children, but the incidence remains low compared to adults. Due to the low rate of thrombotic events in children in general and those various types of TE in particular, large clinical trials regarding epidemiology, risk factors, diagnosis and treatment of these various types of TE are lacking and difficult to carry out in both neonates and children. Most of the recommendations of current guidelines for the general treatment of pediatric TE are extrapolated from adult studies despite several differences between TE in adults and children. It is important to increase knowledge about pediatric thrombosis to improve care in this age group. Therefore, this pediatric registry is needed. Compensation for injuryThe sponsor/investigator has a liability insurance which is in accordance with article 7 of the WMO. Incentives (if applicable)The patients participating in our study will not receive any special incentives, compensationor treatment. Research is combined with routine care and patients will not be approached tovisit the hospital for research purposes only. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATIONHandling and storage of data and documentsAll acquired patient data will be handled confidentially. A subject identification code list will be used to link the data to the subject in every participating center. Only the research group of that center will have access to the source data of the study. The central study database will be anonymized. Data will be kept until 15 years after finishing the study. When data are used for publication they never will be traceable to the individual participants. Handling of data will be done according to the Dutch Personal Data Protection Act. Monitoring and Quality Assurance Not applicableAmendments Amendments are changes made to the research after a favourable opinion by the accredited METC has been given. All amendments will be notified to the METC that gave a favourable opinion. Annual progress reportThe sponsor/investigator will submit a summary of the progress of the trial to the accredited METC once a year. Information will be provided on the date of inclusion of the first subject, numbers of subjects included and numbers of subjects that have completed the trial, serious adverse events/ serious adverse reactions, other problems, and amendments. Temporary halt and (prematurely) end of study reportThe investigator/sponsor will notify the accredited METC of the end of the study within a period of 8 weeks. The end of the study is defined as the last patient’s withdrawal of blood for the coagulation tests. The sponsor will notify the METC immediately of a temporary halt of the study, including the reason of such an action. In case the study is ended prematurely, the sponsor will notify the accredited METC within 15 days, including the reasons for the premature termination. Within one year after the end of the study, the investigator/sponsor will submit a final study report with the results of the study, including any publications/abstracts of the study, to the accredited METC.Public disclosure and publication policyIn accordance with the CCMO statement on publication policy the results of the study will be published unreservedly. As a condition for publication the trial will be registered in a public study registry. REFERENCES ADDIN EN.REFLIST 1.Tuckuviene R, Christensen AL, Helgestad J, Johnsen SP, Kristensen SR. Pediatric venous and arterial noncerebral thromboembolism in Denmark: a nationwide population-based study. J Pediatr. 2011;159(4):663-9.2.van Ommen CH, Heijboer H, Buller HR, Hirasing RA, Heijmans HS, Peters M. Venous thromboembolism in childhood: a prospective two-year registry in The Netherlands. JPediatr. 2001;139(5):676-81.3.Raffini L, Huang YS, Witmer C, Feudtner C. Dramatic increase in venous thromboembolism in children's hospitals in the United States from 2001 to 2007. Pediatrics. 2009;124(4):1001-8.4.Mitchell L, Piovella F, Ofosu F, Andrew M. Alpha-2-macroglobulin may provide protection from thromboembolic events in antithrombin III-deficient children. Blood. 1991;78(9):2299-304.5.Manco-Johnson MJ. Etiopathogenesis of pediatric thrombosis. Hematology. 2005;10 Suppl 1:167-70.6.Rizzi M, Goldenberg N, Bonduel M, Revel-Vilk S, Amankwah E, Albisetti M. Catheter-Related Arterial Thrombosis in Neonates and Children: A Systematic Review. Thromb Haemost. 2018.7.Andrew M, David M, Adams M, Ali K, Anderson R, Barnard D, et al. Venous thromboembolic complications (VTE) in children: first analyses of the Canadian Registry of VTE. Blood. 1994;83(5):1251-7.8.Brandao LR, Simpson EA, Lau KK. Neonatal renal vein thrombosis. Semin Fetal Neonatal Med. 2011;16(6):323-8.9.Jackson BF, Porcher FK, Zapton DT, Losek JD. Cerebral sinovenous thrombosis in children: diagnosis and treatment. Pediatr Emerg Care. 2011;27(9):874-80; quiz 81-3.10.Athale UH, Chan AK. Thrombosis in children with acute lymphoblastic leukemia: part I. Epidemiology of thrombosis in children with acute lymphoblastic leukemia. Thromb Res. 2003;111(3):125-31.11.Klaassen ILM, van Els AL, van de Wetering MD, van Ommen CH. Increasing Incidence and Recurrence Rate of Venous Thromboembolism in Paediatric Oncology Patients in One Single Centre Over 25 Years. Thromb Haemost. 2017;117(11):2156-62.12.Choi SH, Jeong SI, Yang JH, Kang IS, Jun TG, Lee HJ, et al. A single-center experience with intracardiac thrombosis in children with dilated cardiomyopathy. PediatrCardiol. 2010;31(2):264-9.13.Monagle P, Chan AK, Goldenberg NA, Ichord RN, Journeycake JM, Nowak-Gottl U, et al. Antithrombotic therapy in neonates and children: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e737S-e801S.14.Andrew M, Vegh P, Johnston M, Bowker J, Ofosu F, Mitchell L. Maturation of the hemostatic system during childhood. Blood. 1992;80(8):1998-2005.15.Young G, Male C, van Ommen CH. Anticoagulation in children: Making the most of little patients and little evidence. Blood Cells Mol Dis. 2017;67:48-53.16.Andrew M, Marzinotto V, Brooker LA, Adams M, Ginsberg J, Freedom R, et al. Oral anticoagulation therapy in pediatric patients: a prospective study. Thromb Haemost. 1994;71(3):265-9.17.Andrew M, Marzinotto V, Massicotte P, Blanchette V, Ginsberg J, Brill-Edwards P, et al. Heparin therapy in pediatric patients: a prospective cohort study. Pediatr Res. 1994;35(1):78-83.18.Spoor N, Smiers FJ, van der Meer FJ, Hutten BA, van Ommen CH. Phenprocoumon and acenocoumarol treatment in paediatric patients. Thromb Haemost. 2012;108(6).19.Goldenberg NA, Durham JD, Knapp-Clevenger R, Manco-Johnson MJ. A thrombolytic regimen for high-risk deep venous thrombosis may substantially reduce the risk of postthrombotic syndrome in children. Blood. 2007;110(1):45-53.20.Young G, Boshkov LK, Sullivan JE, Raffini LJ, Cox DS, Boyle DA, et al. Argatroban therapy in pediatric patients requiring nonheparin anticoagulation: an open-label, safety, efficacy, and pharmacokinetic study. Pediatr Blood Cancer. 2011;56(7):1103-9.21.Young G, Tarantino MD, Wohrley J, Weber LC, Belvedere M, Nugent DJ. Pilot dose-finding and safety study of bivalirudin in infants <6 months of age with thrombosis. J Thromb Haemost. 2007;5(8):1654-9.22.Young G, Yee DL, O'Brien SH, Khanna R, Barbour A, Nugent DJ. FondaKIDS: a prospective pharmacokinetic and safety study of fondaparinux in children between 1 and 18 years of age. Pediatr Blood Cancer. 2011;57(6):1049-54.23.Massicotte P, Julian JA, Gent M, Shields K, Marzinotto V, Szechtman B, et al. An open-label randomized controlled trial of low molecular weight heparin compared to heparin and coumadin for the treatment of venous thromboembolic events in children: the REVIVE trial. Thromb Res. 2003;109(2-3):85-92.24.Monagle P, Cochrane A, Roberts R, Manlhiot C, Weintraub R, Szechtman B, et al. A multicenter, randomized trial comparing heparin/warfarin and acetylsalicylic acid as primary thromboprophylaxis for 2 years after the Fontan procedure in children. J Am Coll Cardiol. 2011;58(6):645-51.25.Massicotte P, Julian JA, Gent M, Shields K, Marzinotto V, Szechtman B, et al. An open-label randomized controlled trial of low molecular weight heparin for the prevention of central venous line-related thrombotic complications in children: the PROTEKT trial. ThrombRes. 2003;109(2-3):101-8.26.Halton JML, Albisetti M, Biss B, Bomgaars L, Brueckmann M, Gropper S, et al. Phase IIa study of dabigatran etexilate in children with venous thrombosis: pharmacokinetics, safety, and tolerability. J Thromb Haemost. 2017;15(11):2147-57.27.Mitchell LG, Goldenberg NA, Male C, Kenet G, Monagle P, Nowak-Gottl U, et al. Definition of clinical efficacy and safety outcomes for clinical trials in deep venous thrombosis and pulmonary embolism in children. J Thromb Haemost. 2011;9(9):1856-8.APPENDIX 1Participating centers with principal investigators:M. Albisetti , University Children's Hospital, Zurich, SwitzerlandM. Bhatt, McMaster Children's Hospital, McMaster University, Hamilton, Ontario, CanadaM. Bonduel, Hospital de Pediatría Prof. Dr. Juan P. Garrahan, Buenos Aires, ArgentinaB. Branchford, Children's Hospital Colorado, Aurora, CO, USAE. Chalmers, Royal Hospital for Children, Glasgow, UKS. Holzhauer, Charité University Medicine, Berlin, GermanyC. Male, Medical University of Vienna, Vienna, AustriaP. Monagle, Royal Children's Hospital, Parkville, Victoria, AustraliaU. Nowak-Gottl, University Hospital Schleswig-Holstein, Kiel, GermanyC. van Ommen, Sophia Childrens’’s Hospital ErasmusMC, Rotterdam, the NetherlandsS. Revel-Vilk, Shaare Zedek Medical Center- Affiliated with Hadassah- Hebrew University Medical School, Jerusalem, Israel More centers will participate in the coming yearsAPPENDIX 2Datasheet General thrombosis databaseInternational Pediatric Thrombosis NetworkCenter number:Patient number:General informationAge at diagnosis of thrombosis: ………….. years, ………months, ………daysGender:?Female?MaleType of thrombosis*:?venous?arterialLocation*:?upper extremity?lower extremity?inferior caval vein?superior caval vein?kidney (if marked, go to sheet renal vein thrombosis)?lung?liver? intracardiac? intracranialother, namely…………………………………….Risk factors*:?central venous catheter?(congenital) heart disease?oral contraceptives?malignancy?infection?surgery?immobility?renal disease?obesity? arterial catheter? previous thrombotic event? thrombophilia? positive family history? maternal or delivery factors, if yes specify………?other, namely…………………………..Treatment*:?no antithrombotic treatment?unfractionated heparin?LMWH, if yes which type:? enoxaparin? dalteparin? nadroparin? tinzaparin?vitamin K antagonist, if yes which type:? warfarin? acenocoumarol? phenprocoumon?argatroban?fondaparinux?bilivarudin?DOAC, if yes which type:? rivaroxaban? dabigatran? apixaban? edoxaban?thrombolysis, if yes which type: ? r-TPA? urokinase? streptokinase?antiplatelet drugs, if yes, which?...............................?other, namely………………………………………………..*mark all applicableAPPENDIX 3Renal vein thrombosis(*mark all applicable)BASELINE CHARACTERISTICSDate renal vein thrombosis (RVT)dd/mm/yyyyPresentation*?macroscopic hematuria?palpable abdominal mass?thrombocytopenia?renal insufficiency?other symptoms:…………………………………..Risk factors*?asphyxia#If yes: Apgar score 1 min:……. Apgar score 5 min:…….?maternal diabetes?shock&?prematurityIf yes: gestational age:……….weeks,……….days?sepsis°If yes:? bacteria:………………………….? virus:………………………………..? fungus:……………………………..?others: …………………………………………………………ThrombophiliaThrombophilia tested:? no? yesIf yes, date of testing: dd/mm/yyyyConfirmation testing date of deficiency: dd/mm/yyyy If yes, results?:FVLeiden mutation heterogeous? present? not present? not testedFVLeiden homozygeous? present? not present? not testedFII mutation heterozygeous? present? not present? not testedFII mutation homozygeous? present? not present? not testedCongenital antithrombin deficiency? present? not present? not testedCongenital protein S deficiency? present? not present? not testedCongenital protein C deficiency? present? not present? not testedDiagnostic methods*? Ultrasonography? CT scan? Other:………………………………………………Characteristics of renal vein thrombosis*? right renal vein? left renal vein? bilateral? involvement inferior caval vein? pulmonary embolism? involvement other veinsIf yes, which? ……………………….? adrenal hemorrhage present? other:……………………………………………. ................
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