Clinical Trials Register

Summary
EudraCT Number:	2015-002610-76
Sponsor's Protocol Code Number:	39039039CHD3001/BAY59-7939-18226
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-08-01
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

France - ANSM

A.2

EudraCT number

2015-002610-76

A.3

Full title of the trial

A Prospective, Open-Label, Active-Controlled Study to Evaluate the Pharmacokinetics, Pharmacodynamics, Safety, and Efficacy of Rivaroxaban for Thromboprophylaxis in Pediatric Subjects 2 to 8 Years of Age after the Fontan Procedure

Etude prospective, en ouvert, contrôlée versus traitement actif, pour évaluer la pharmacocinétique, la pharmacodynamie, la sécurité d’emploi et l’efficacité du rivaroxaban dans la thromboprophylaxie chez des patients âgés de 2 à 8 ans, ayant subi une procédure de Fontan

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A Study to Evaluate the Pharmacokinetics, Pharmacodynamics, Safety, and Efficacy of Rivaroxaban for Thromboprophylaxis in Pediatric Subjects 2 to 8 Years of Age after the Fontan Procedure

Etude pour évaluer la pharmacocinétique, la pharmacodynamie, la sécurité et l'efficacité du rivaroxaban dans la prophykaxie des thromboses, chez les enfants âgés de 2 à 8 ans ayant subi une procédure de Fontan ou dérivation cavopulmonaire totale (DCPT)

A.3.2

Name or abbreviated title of the trial where available

UNIVERSE

A.4.1

Sponsor's protocol code number

39039039CHD3001/BAY59-7939-18226

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Janssen-Cilag International N.V
B.1.3.4	Country	Belgium
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Janssen Research & Development, LLC
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Janssen Research and Development, LLC
B.5.2	Functional name of contact point	Liza Miriam Pina, MD
B.5.3	Address:
B.5.3.1	Street Address	920 US Highway 202 S
B.5.3.2	Town/ city	Raritan
B.5.3.3	Post code	08869
B.5.3.4	Country	United States
B.5.4	Telephone number	+1908927 5322
B.5.6	E-mail	lpina5@its.jnj.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Xarelto
D.3.2	Product code	JNJ-39039039; BAY 59-7939
D.3.4	Pharmaceutical form	Granules for oral solution
D.3.4.1	Specific paediatric formulation	Yes
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	RIVAROXABAN
D.3.9.1	CAS number	366789-02-8
D.3.9.2	Current sponsor code	JNJ-39039039; BAY 59-7939
D.3.9.4	EV Substance Code	SUB29263
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Aspirin
D.2.1.1.2	Name of the Marketing Authorisation holder	actavis / Hexal
D.2.1.2	Country which granted the Marketing Authorisation	Germany
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	acetylsalicylic acid
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ACETYLSALICYLIC ACID
D.3.9.1	CAS number	50-78-2
D.3.9.4	EV Substance Code	SUB12730MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

thromboprophylaxis

E.1.1.1

Medical condition in easily understood language

thromboprophylaxis

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10040729
E.1.2	Term	Single ventricle
E.1.2	System Organ Class	100000004850

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

Part A
To characterize the single- and multiple-dose PK and PK/ PD profiles after oral rivaroxaban therapy administered to pediatric subjects 2 to 8 years of age with single ventricle physiology who have completed the Fontan procedure within 4 months prior to enrollment.

Part B
To evaluate the safety and efficacy of rivaroxaban, administered twice daily (exposure matched to rivaroxaban 10 mg once daily in adults) compared to ASA, given once daily (approximately 5 mg/kg) for thromboprophylaxis in pediatric subjects 2 to 8 years of age with single ventricle physiology who have completed the Fontan procedure within 4 months prior to enrollment.

E.2.2

Secondary objectives of the trial

Part A
To assess the safety and tolerability of rivaroxaban treatment.

Part B
To further characterize the PK and PK/PD profiles of rivaroxaban.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Boys or girls 2 to 8 years of age with single ventricle physiology and who have completed the initial Fontan procedure within 4 months prior to enrollment
2. Considered to be clinically stable by the investigator and able to tolerate oral or enteral administration of a suspension formulation and oral/enteral feedings
3. Satisfactory initial post-Fontan transthoracic echocardiographic screening as defined in the Post-Fontan Echocardiographic Examination Research Protocol
4. Parent/legally acceptable representative must sign an informed consent form (ICF) and child assent will also be provided, if applicable, according to local requirements.

E.4

Principal exclusion criteria

1. Evidence of thrombosis, including those that are asymptomatic confirmed by post-Fontan procedure transthoracic echocardiogram, or other imaging techniques, during the screening period of the study
2. History of gastrointestinal disease or surgery associated with clinically relevant impaired absorption
3. History of or signs/symptoms suggestive of protein-losing enteropathy
4. Active bleeding or high risk for bleeding contraindicating antiplatelet or anticoagulant therapy, including a history of intracranial bleeding
5. Indication for anticoagulant or antiplatelet therapy other than current study, however:
- A subject who has received VKA after the Fontan procedure may be eligible provided that the subject has discontinued VKA before the screening visit. Baseline laboratory samples must be obtained at least 7 days after the last dose of VKA.
- A subject who is receiving ASA at the time of the screening visit may be eligible and may continue on ASA provided the last dose is taken at least 24 hours prior to the first dose of study drug.
6. Platelet count <50 x 10^9/L at screening.
7. Creatinine clearance (CrCl) <30 mL/min/1.73m2.
8. Known clinically significant liver disease.

E.5 End points

E.5.1

Primary end point(s)

Part A:
PK and PD Parameters: PT, aPTT and anti-FXa activity against Rivaroxaban plasma concentration.
PK: AUC (O-24), Cmax after single dose and AUC (0-24), Cmax and Cmin at steady state

Part B:
Efficacy: Thrombotic events (venous or arterial), defined as:
- The appearance of a new thrombotic burden within the cardiovascular system on either routine surveillance or clinically indicated imaging, or
- The occurrence of a clinical event known to be strongly associated with thrombus (such as cardioembolic stroke, pulmonary embolism).
Safety: major bleeding events as defined by ISTH

E.5.1.1

Timepoint(s) of evaluation of this end point

Part A:
Day 1, 4, Month 3, 12

Part B:
Ongoing throughout the study as well as at pre-defined time points (Day 12, Months 3, 6 and 12) from enrollment until final follow-up phone call

E.5.2

Secondary end point(s)

Part A:
Efficacy: Thrombotic events (venous or arterial), defined as:
- The appearance of a new thrombotic burden within the cardiovascular system on either routine surveillance or clinically indicated imaging, or
- The occurrence of a clinical event known to be strongly associated with thrombus (such as cardioembolic stroke, pulmonary embolism).
Any death
Safety: major bleeding events, Clinically relevant non-major bleeding events and trivial (minimal) bleeding as defined by ISTH; other adverse events and clinical laboratory test values (CBC, CrCl, liver function tests, and PT and aPTT).

Part B:
PK/PD Parameters: PT, aPTT and anti-FXa activity against Rivaroxaban plasma concentration.
PK: AUC (O-24), Cmax after single dose and AUC (0-24), Cmax and Cmin at steady state
Safety: Clinically relevant non-major bleeding events and trivial (minimal) bleeding as defined by ISTH; any death, other adverse events and clinical laboratory test values(CBC, CrCl, liver function tests, and PT and aPTT) .

E.5.2.1

Timepoint(s) of evaluation of this end point

Part A:
Ongoing throughout the study as well as at pre-defined time points (Day 12, Months 3, 6 and 12) from enrollment until final follow-up examination

Part B:
Day 1, Month 3, Month 12

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Argentina

Australia

Belgium

Brazil

Canada

China

France

Japan

Korea, Republic of

Malaysia

Mexico

Netherlands

Spain

Thailand

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

The study is considered completed with the last scheduled study contact shown in the Time and Events Schedule for the last subject participating in the study.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

100

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

100

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

100

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Not applicable

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2017-01-25

Ethics Committee Opinion of the trial application

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

P. End of Trial
P.	End of Trial Status	Completed

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IMP with orphan designation in the indication
Orphan Designation Number:
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