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NLxxxxx.xxx.xx / Throm-PED Registry Pediatric thrombosis

Observational study of pediatric thrombotic disease: the Throm-PED registry

Scientific Subcommittee Pediatric and Neonatal Hemostasis and Thrombosisof the International Society of Thrombosis and Haemostasis

Throm-PED Registry- IPTN – version 1 - 19062018


PROTOCOL TITLE ‘Observational study of pediatric thrombotic disease: the Throm-PED registry’

Protocol ID Throm-PED 2018

Short title Throm-PED registry

Version 1

Date 19-06-2018

Coordinating investigator/project leader

On behalf of IPTN

Dr CH van Ommen, chair steering committee IPTN

Principal 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 party None

Independent expert (s) For our center :…..



PROTOCOL SIGNATURE SHEET

Name Signature Date

Sponsor or legal representative:…………..

Head of Department:…………………..

[Coordinating Investigator/Project leader/Principal Investigator]:Steering committee IPTN

Chair Dr CH van Ommen



TABLE OF CONTENTS

1. INTRODUCTION AND RATIONALE...............................................................................101.1 General background thromboembolic disease in children.......................................101.2 Research in pediatric patients with specific thrombotic events................................111.3 The use, effectiveness and safety of antithrombotic agents....................................111.4 The International Pediatric Thrombosis Network.....................................................121.5 Rationale..................................................................................................................13

2. OBJECTIVES..................................................................................................................133. STUDY DESIGN..............................................................................................................134. STUDY POPULATION....................................................................................................14

4.1 Population (base).....................................................................................................144.2 Inclusion criteria........................................................................................................144.3 Exclusion criteria......................................................................................................14

5. TREATMENT OF SUBJECTS.........................................................................................146. INVESTIGATIONAL PRODUCT......................................................................................147. NON-INVESTIGATIONAL PRODUCT.............................................................................148. METHODS.......................................................................................................................14

8.1 Main study parameters/endpoints............................................................................148.2 Secondary study parameters/outcomes...................................................................158.3 Study procedures.....................................................................................................16

8.3.1 Recruitment.......................................................................................................168.3.2 Data collection...................................................................................................16

8.4 Withdrawal of individual subjects..............................................................................178.5 Replacement of individual subjects after withdrawal................................................178.6 Follow-up of subjects withdrawn from treatment......................................................178.7 Premature termination of the study..........................................................................17

9. SAFETY REPORTING....................................................................................................179.1 Temporary halt for reasons of subject safety...........................................................179.2 AEs, SAEs................................................................................................................189.3 Annual safety report.................................................................................................189.4 Follow-up of adverse events.....................................................................................18

10. STATISTICAL ANALYSIS............................................................................................1810.1 Selection of subjects for analysis.............................................................................1810.2 Analysis....................................................................................................................19

11. ETHICAL CONSIDERATIONS.....................................................................................1911.1 Regulation statement................................................................................................1911.2 Recruitment and consent..........................................................................................1911.3 Objection by minors or incapacitated subjects (if applicable)...................................1911.4 Benefits and risks assessment, group relatedness..................................................2011.5 Compensation for injury............................................................................................2011.6 Incentives (if applicable)...........................................................................................20

12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION..........................20



12.1 Handling and storage of data and documents..........................................................2012.2 Monitoring and Quality Assurance...........................................................................2112.3 Amendments............................................................................................................2112.4 Annual progress report.............................................................................................2112.5 Temporary halt and (prematurely) end of study report.............................................2112.6 Public disclosure and publication policy...................................................................21

13. REFERENCES.............................................................................................................22



LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS

ABR ABR 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)

AE Adverse Event

ALL Acute Lymphoblastic Leukemia

CA Competent Authority

CCMO Central Committee on Research Involving Human Subjects; in Dutch: Centrale

Commissie Mensgebonden Onderzoek

CRNM Clinically relevant non major

CV Curriculum Vitae

DOAC Direct Oral AntiCoagulant

DSMB Data Safety Monitoring Board

EU European Union

GCP Good Clinical Practice

IC Informed Consent

IMP Investigational Medicinal Product

IPTN International Pediatric Thrombosis Network

ISTH International Society of Thrombosis and Haemostasis

LMWH Low-molecular-weight heparin

METC Medical research ethics committee (MREC); in Dutch: medisch ethische toetsing

commissie (METC)

RCT Randomized controlled trial

(S)AE (Serious) Adverse Event

Sponsor The sponsor is the party that commissions the organisation or performance of the

research, for example a pharmaceutical

company, academic hospital, scientific organisation or investigator. A party that

provides funding for a study but does not commission it is not regarded as the

sponsor, but referred to as a subsidising party.

SSC Scientific SubCommittee

SVT Sinovenous thrombosis

TE Thromboembolic event

VKA Vitamin K antagonist

VTE Venous thromboembolic event

Wbp Personal Data Protection Act (in Dutch: Wet Bescherming Persoonsgevens)

WMO Medical Research Involving Human Subjects Act (in Dutch: Wet Medisch-

Throm-PED Registry version 2018-01, 2018-5-1 6 of 27


wetenschappelijk Onderzoek met Mensen



SUMMARY

Rationale: 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 study

Study population: (Preterm) neonates, infants, children and adolescents (0-18 years old)

with thromboembolic disease

Main 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.



1. INTRODUCTION AND RATIONALE

1.1 General 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.(1, 2) Among

hospitalized pediatric patients, the incidence of VTE is approximately 20 to 60 per 10,000

admissions.(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.(4)

In general, VTE is typically diagnosed in hospitalized children, especially critically ill

neonates with catheters and adolescents with a combination of risk factors.(2, 5) These risk

factors may include catheters, malignancy, cardiac disease, infection, surgery, immobility,

and obesity. Nearly all cases of arterial thrombosis are associated with arterial catheters.(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.(7) In addition, VTE also occurs in the central

nervous system (CNS) and in vessels associated with specific organs.(8, 9) Furthermore,

there are clearly defined disease processes that are associated with an increased risk of

VTEs, which are often located in specific organs such as left ventricle thrombosis in patients

with dilated cardiomyopathy or sinovenous thrombosis (SVT) in patients with acute

lymphoblastic leukemia (ALL).(10-12) The majority of these VTEs have their own

pathophysiologic conditions, risk factors, age and sex distribution, and diagnostic and

therapeutic approach.

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 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.(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.(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.(15) Treatment of arterial TE depends on the location of thrombosis and may

consist of platelet aggregation inhibitors or anticoagulation agents.(13) Recommendations

about dosages, efficacy and safety of these drugs are based on mostly small, retrospective

cohort studies.(16-22) Despite important efforts to perform international trials, few

randomized controlled trials (RCTs) have been performed. Most of these RCTs were stopped

prematurely due to inclusion problems.(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.(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.(26)

1.2 Research in pediatric patients with specific thrombotic events

Despite 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.

1.3 The use, effectiveness and safety of antithrombotic agents

In 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.

1.4 The International Pediatric Thrombosis Network

The 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

(i) 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;

(ii) 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.

1.5 Rationale

The 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.

2. OBJECTIVES

Primary 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 TE

Secondary 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 TE

3. STUDY DESIGN



This 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.

4. STUDY POPULATION

4.1 Population (base)

(Preterm) neonates, infants, children and adolescents (0-18 years old) with thromboembolic disease are eligible for this prospective cohort study.

4.2 Inclusion criteria

In 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 procedures

4.3 Exclusion criteria

A potential subject who meets any of the following criteria will be excluded from participation in this study:1. Patients older than 18 years of age at the time of thromboembolic disease2. Patients without written informed consent

5. TREATMENT OF SUBJECTSThe included patients with TE will be treated according to the treating physician’s discretion.

6. INVESTIGATIONAL PRODUCT Not applicable

7. NON-INVESTIGATIONAL PRODUCTNot applicable

8. METHODS

8.1 Main 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.

Bleeding definitions, are based on the definitions as defined by the Perinatal and Paediatric

Haemostasis SSC of the ISTH.(27)

Major bleeding is defined as a composite (ie, any) of the following:

Fatal bleeding

Clinically overt bleeding associated with a decrease in hemoglobin of at least 20

g/L (ie, 2 g/dL) in a 24-hour period

Bleeding that is retroperitoneal, pulmonary, intracranial, or otherwise involves the

central nervous system

CRNM 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 condition

Bleeding that requires medical or surgical or percutaneous intervention to restore

hemostasis, other than in an operating suite

8.2 Secondary study parameters/outcomes

1. the frequency and types of various treatment options over time in various TE

2. The 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 thrombosis



8.3 Study procedures

8.3.1 RecruitmentPotential 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.

8.3.2 Data collection

Baseline 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.

(www.redcap.isth.org)

Baseline Data collection may include:

Contact email address of principal investigator

Demographic information: age, gender

Family history of thrombosis

Type of thrombosis

Presentation

Diagnostic methods

Location of thrombosis

Risk factors, such as thrombophilia, associated conditions

Treatment of thrombosis

After 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 Data



Current and interval medication exposure

Reasons for changes in medication regimen

Complications antithrombotic therapy including bleeding complications

Short term outcomes including death, recurrent thrombosis, and thrombotic burden

Long term outcomes including post thrombotic syndrome and thrombotic burden

Outcome 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.

8.4 Withdrawal of individual subjects

Subjects can leave the study at any time for any reason if they wish to do so without any consequences. The investigator can decide to withdraw a subject from the study for urgent medical reasons.

8.5 Replacement of individual subjects after withdrawal

Not applicable

8.6 Follow-up of subjects withdrawn from treatment

Not applicable

8.7 Premature termination of the studyNot applicable

9. SAFETY REPORTING

9.1 Temporary 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.

9.2 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.

9.3 Annual safety reportNot applicable

9.4 Follow-up of adverse eventsNot applicable

10. STATISTICAL 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.

10.1 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).

10.2 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 associated



with 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.

11. ETHICAL CONSIDERATIONS

11.1 Regulation 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.

11.2 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.

11.3 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.



11.4 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.

11.5 Compensation for injuryThe sponsor/investigator has a liability insurance which is in accordance with article 7 of the

WMO.

11.6 Incentives (if applicable)The patients participating in our study will not receive any special incentives, compensation

or treatment. Research is combined with routine care and patients will not be approached to

visit the hospital for research purposes only.

12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION

12.1 Handling 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.

12.2 Monitoring and Quality Assurance Not applicable



12.3 Amendments 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.

12.4 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.

12.5 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.

12.6 Public disclosure and publication policy

In 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.



13. REFERENCES

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 1

Participating centers with principal investigators:

M. Albisetti , University Children's Hospital, Zurich, Switzerland

M. Bhatt, McMaster Children's Hospital, McMaster University, Hamilton, Ontario, Canada

M. Bonduel, Hospital de Pediatría Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina

B. Branchford, Children's Hospital Colorado, Aurora, CO, USA

E. Chalmers, Royal Hospital for Children, Glasgow, UK

S. Holzhauer, Charité University Medicine, Berlin, Germany

C. Male, Medical University of Vienna, Vienna, Austria

P. Monagle, Royal Children's Hospital, Parkville, Victoria, Australia

U. Nowak-Gottl, University Hospital Schleswig-Holstein, Kiel, Germany

C. van Ommen, Sophia Childrens’’s Hospital ErasmusMC, Rotterdam, the Netherlands

S. Revel-Vilk, Shaare Zedek Medical Center- Affiliated with Hadassah- Hebrew University Medical School, Jerusalem, Israel

More centers will participate in the coming years



APPENDIX 2

Datasheet

General thrombosis database

International Pediatric Thrombosis Network

Center number:Patient number:

General informationAge at diagnosis of thrombosis: ………….. years, ………months, ………daysGender: ⃝ Female⃝ Male

Type of thrombosis*: ⃝ venous⃝ arterial

Location*: ⃝ upper extremity⃝ lower extremity⃝ inferior caval vein⃝ superior caval vein⃝ kidney (if marked, go to sheet renal vein thrombosis)⃝ lung⃝ liver⃝ intracardiac⃝ intracranialother, namely…………………………………….



Risk factors*: ⃝ central venous catheter⃝ (congenital) heart disease⃝ oral contraceptives⃝ malignancy⃝ infection⃝ surgery⃝ immobility⃝ renal disease⃝ obesity⃝ arterial catheter⃝ previous thrombotic event⃝ thrombophilia⃝ positive family history⃝ maternal or delivery factors, if yes specify………

⃝ other, namely…………………………..

Treatment*: ⃝ no antithrombotic treatment⃝ unfractionated heparin⃝ LMWH, if yes which type: enoxaparin⃝ dalteparin⃝ nadroparin⃝ tinzaparin⃝⃝ vitamin K antagonist, if yes which type: warfarin⃝

acenocoumarol⃝ phenprocoumon⃝⃝ argatroban⃝ fondaparinux⃝ bilivarudin⃝ DOAC, if yes which type: rivaroxaban⃝

dabigatran⃝ apixaban⃝ edoxaban⃝⃝ thrombolysis, if yes which type: r-TPA ⃝ urokinase⃝ streptokinase⃝⃝ antiplatelet drugs, if yes, which?...............................⃝ other, namely………………………………………………..

*mark all applicable



APPENDIX 3

Renal 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

⃝ yes

If yes, date of testing: dd/mm/yyyyConfirmation testing date of deficiency: dd/mm/yyyy



If yes, results£:FVLeiden mutation heterogeous ⃝ present

⃝ not present⃝ not tested

FVLeiden homozygeous ⃝ present⃝ not present⃝ not tested

FII mutation heterozygeous ⃝ present⃝ not present⃝ not tested

FII mutation homozygeous ⃝ present⃝ not present⃝ not tested

Congenital antithrombin deficiency ⃝ present⃝ not present⃝ not tested

Congenital protein S deficiency ⃝ present⃝ not present⃝ not tested

Congenital protein C deficiency ⃝ present⃝ not present⃝ not tested

Diagnostic methods* ⃝ Ultrasonography⃝ CT scan

⃝ Other:………………………………………………

Characteristics of renal vein thrombosis* ⃝ right renal vein

⃝ left renal vein

⃝ bilateral

⃝ involvement inferior caval vein

⃝ pulmonary embolism

⃝ involvement other veins

If yes, which? ……………………….

⃝ adrenal hemorrhage present

⃝ other:…………………………………………….


instructions for use ‘template research protocol’ · web view27.mitchell lg, goldenberg na,...

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