Clinical Trials Register

Summary
EudraCT Number:	2013-004484-31
Sponsor's Protocol Code Number:	Riva-PCC
National Competent Authority:	Austria - BASG
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-11-13
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

Austria - BASG

A.2

EudraCT number

2013-004484-31

A.3

Full title of the trial

Rivaroxaban and PCC: Prothrombin Complex Concentrate in patients with bleeding complications related to Rivaroxaban

Eine prospektive klinische Pilotstudie zur Untersuchung der Wirksamkeit von Prothrombin Komplex Konzentraten (Beriplex®) bei Patienten mit Blutungskomplikationen unter der Einnahme von Rivaroxaban (Xarelto®)

A.3.1

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

Rivaroxaban and PCC: Prothrombin Complex Concentrate (Beriplex®) in patients with bleeding complications related to Rivaroxaban (Xarelto®)

Rivaroxaban und PCC: Die Wirksamkeit von Prothrombin Komplex Kontentraten (Beriplex®) bei Patienten mit Blutungskomplikationen unter der Therapie mit Rivaroxaban (Xarelto®)

A.3.2

Name or abbreviated title of the trial where available

Riva-PCC

A.4.1

Sponsor's protocol code number

Riva-PCC

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	Medizinische Universität Innsbruck / Allg. u. chirug. Intensivmedizin
B.1.3.4	Country	Austria
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Medizinische Universität Innsbruck
B.4.2	Country	Austria
B.4.1	Name of organisation providing support	CSL Behring
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Medizinische Universität Innsbruck / Univ.-Klinik für Allg. u.l Chirurg. Intensivmedizin
B.5.2	Functional name of contact point	Projektmanagement
B.5.3	Address:
B.5.3.1	Street Address	Anichstraße 35
B.5.3.2	Town/ city	Innsbruck
B.5.3.3	Post code	6020
B.5.3.4	Country	Austria
B.5.4	Telephone number	004351250424635
B.5.5	Fax number	004351250427793
B.5.6	E-mail	bettina.schenk@i-med.ac.at

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	Yes
D.2.1.1.1	Trade name	Xarelto
D.2.1.1.2	Name of the Marketing Authorisation holder	Bayer Pharma AG
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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.3.4	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	RIVAROXABAN
D.3.9.1	CAS number	366789-02-8
D.3.9.4	EV Substance Code	SUB29263
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	10
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	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	Yes
D.2.1.1.1	Trade name	Beriplex
D.2.1.1.2	Name of the Marketing Authorisation holder	CSL Behring
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.3.4	Pharmaceutical form	Powder and solvent for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous bolus use (Noncurrent) Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Humaner Blutgerinnungsfaktor II
D.3.9.3	Other descriptive name	HUMAN COAGULATION FACTOR II
D.3.9.4	EV Substance Code	SUB41201
D.3.10	Strength
D.3.10.1	Concentration unit	IU/ml international unit(s)/millilitre
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	20 to 48
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Humaner Blutgerinnungsfaktor VII
D.3.9.3	Other descriptive name	HUMAN COAGULATION FACTOR VII
D.3.9.4	EV Substance Code	SUB13811MIG
D.3.10	Strength
D.3.10.1	Concentration unit	IU/ml international unit(s)/millilitre
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	10 to 25
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Humaner Blutgerinnungsfaktor IX
D.3.9.3	Other descriptive name	HUMAN COAGULATION FACTOR IX
D.3.9.4	EV Substance Code	SUB12030MIG
D.3.10	Strength
D.3.10.1	Concentration unit	IU/ml international unit(s)/millilitre
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	20 to 31
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Humaner Blutgerinnungsfaktor X
D.3.9.3	Other descriptive name	HUMAN COAGULATION FACTOR X
D.3.9.4	EV Substance Code	SUB41252
D.3.10	Strength
D.3.10.1	Concentration unit	IU/ml international unit(s)/millilitre
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	22 to 60
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Protein C
D.3.9.3	Other descriptive name	PROTEIN C
D.3.9.4	EV Substance Code	SUB12567MIG
D.3.10	Strength
D.3.10.1	Concentration unit	IU/ml international unit(s)/millilitre
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	15 to 45
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Protein S
D.3.9.3	Other descriptive name	PROTEIN S
D.3.9.4	EV Substance Code	SUB22287
D.3.10	Strength
D.3.10.1	Concentration unit	IU/ml international unit(s)/millilitre
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	12 to 38
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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

blood coagulation disorder

Blutgerinnungsstörungen

E.1.1.1

Medical condition in easily understood language

treatment of bleeding

Behandlung von Blutungen

E.1.1.2

Therapeutic area

Diseases [C] - Blood and lymphatic diseases [C15]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.1
E.1.2	Level	HLT
E.1.2	Classification code	10009728
E.1.2	Term	Coagulation and bleeding analyses
E.1.2	System Organ Class	100000004848

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Assessment of effective reversal of Rivaroxaban (Xarelto) with Prothrombin Complex Concentrate (Beriplex)

Feststellung der erfolgreichen Reversierung von Rivaroxaban (Xarelto) mittels Prothrombin Komplex Konzentrat (Beriplex)

E.2.2

Secondary objectives of the trial

Assessment of the differences in the response profile of the following parameters:
- Coagulation status
- Coagulation factor profile
- Standard coagulation tests
- Functional coagulation tests
- Inflammation profile
- Other biological and clinical parameters
- differences between groups

Beurteilung der Unterschiede im Antwortprofil folgender Paramater:
- Gerinnungsstatus
- Gerinnungsfaktoren Profil
- Standard Gerinnungsanalysen
- Funktionelle Gerinnungsanalysen
- Entzündungsprofil
- Weitere biologische und klinische Parameter
- Unterschiede zwischen den Gruppen

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

I.1. Patient at the obvious age of ≥ 18 years of either sex
I.2. Patients receiving Rivaroxaban
I.3.a Patients with significant bleeding with the need of reversal
AND/OR
I.3.b Patients needing acute reversal of rivaroxaban anticoagulation effects

I.1. Patienten beider Geschlechter ab dem vollendeten 18. Lebensjahr
I.2. Patienten unter der Therapie mit Rivaroxaban
I.3.a Patienten mit signifikanten Blutungen mit Bedarf an Reversierung
AND/OR
I.3.b Patienten mit Bedarf an akuter Reversierung der Antikoagulatorischen Effekte von Rivaroxaban

E.4

Principal exclusion criteria

E.1. Additional treatment with further procoagulant therapy including recombinant activated factor seven, FEIBA or other coagulation factor concentrates (except fibrinogen concentrate, DDAVP and tranexamic acid)
E.2. Risk for thromboembolic events higher than the bleeding risk as anticipated by the physician
E.3. Pregnant or nursing women
for emergency patients: obviously pregnant women
E.4. Patient with suspected or confirmed sepsis
E.5. Patient with known recent history of thromboembolic events within the last 3 months
E.6. Patients who disagree to participate in the study
for emergency patients: patients with known refusal of a participation in this clinical trial
E.7. Known active participation in a clinical trial
E.8. Any condition, including the presence of laboratory abnormalities, which would place the subject at unacceptable risk if he/she would participate in the study or confound in the ability to interpret data from the study
E.9. Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form

E.1. Therapie mit weiteren prokoagulatorischen Medikamenten wie
Faktor II, FEIBA oder andere Gerinnungsfaktor Konzentrate
(mit Ausnahme von Fibrinogenkonzentrat, DDAVP und
Tranexamsäure)
E.2. Vorliegen eines höheren Risikos für das Auftreten eines thromb-
embolischen Geschehens als für eine Blutung
E.3. Schwangere und stillende Frauen
im Notfall: offensichtlich schwangere Frauen
E.4. Patienten mit vermuteter oder diagnostizierter Sepsis
E.5. Patienten mit anamnestischem thrombembolischen Ereignis in den
vergangenen 3 Monaten
E.6. Patienten, die einer Inkludierung nicht zustimmen
E.7. Patienten, die bereits in einer anderen klinischen Studie inkludiert
sind
E.8. Das Vorliegen eines bestimmten Zustandes, inklusive
pathologischer Laborwerte, durch welchen der Patient im Falle einer
Inkludierung einem unakzeptablen Risiko ausgesetzt werden würde
E.9. Das Vorliegen eines bestimmten medizinischen Zustandes, einer
Laborabnormalität oder psychiatrischen Erkrankung, wodurch es dem
Patienten unmöglich wäre der Inkludierung einzuwilligen

E.5 End points

E.5.1

Primary end point(s)

Difference in the thrombin generation between t1 and t2

Wie verändert sich die Thrombingeneration zwischen t1 und t2

E.5.1.1

Timepoint(s) of evaluation of this end point

between t1 and t2

zwischen t1 und t2

E.5.2

Secondary end point(s)

Developing of following parameters from V1 to V10 in correlation with blood level of Rivaroxaban (Xarelto®) and thrombin generation:
- Thrombin generation
- Single factor profiles
- Standard coagulation tests outcome (PT, aPTT, fibrinogen, AT, etc.)
- ROTEM® results (FibTEM, ExTEM, InTEM, HepTEM)
- Further biological parameters
- Differences between sample groups

Das Verhalten folgender Parameter von V1 bis V10 in Korrelation mit dem Blutspiegel von Rivaroxaban (Xarelto®) und der Thrombingeneration:
- Thrombingeneration
- Profil der Gerinnungsfaktoren
- Standard Gerinnungstests (PT, aPTT, Fibrinogen, AT, etc.)
- ROTEM® (FibTEM, EcaTEM, ExTEM, InTEM, HepTEM)
- Weitere biologische Parameter
- Unterschiede zwischen den Gruppen

E.5.2.1

Timepoint(s) of evaluation of this end point

from V1 to V10

von V1 bis V10

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

Yes

E.6.4

Safety

E.6.5

Efficacy

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

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)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

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)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

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

Last Patient Last Visit (LPLV)

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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

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)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

Yes

F.3.3.1

Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2013-11-13.

Yes

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

Yes

F.3.3.5

Emergency situation

Yes

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Patients under Rivaroxaban (Xarelto) treatment with major, life-threatening bleeding events will be treated with Prothrombin Complex Concentrate (Beriplex).

Patienten in Behandlung mit Rivaroxaban, welche unter lebensbedrohlichen Blutungen eingeliefert werden und mit Prothrombin Komplex Konzentrat (Beriplex) behandelt werden.

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

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)

The post-treatment is not different from the expected normal treatment for that condition.

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

2013-12-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-01-10

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-10-21

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