Clinical Trials Register

Summary
EudraCT Number:	2007-007861-19
Sponsor's Protocol Code Number:	BE1116_3002
National Competent Authority:	Bulgarian Drug Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2009-01-13
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

Bulgarian Drug Agency

A.2

EudraCT number

2007-007861-19

A.3

Full title of the trial

An open-label, randomized, multicenter Phase IIIb study to assess the efficacy, safety and tolerance of BERIPLEX® P/N compared with plasma for rapid reversal of
coagulopathy induced by coumarin derivatives in subjects with acute major bleeding

A.4.1

Sponsor's protocol code number

BE1116_3002

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	CSL Behring GmbH
B.1.3.4	Country	Germany
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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

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	Beriplex P/N
D.2.1.1.2	Name of the Marketing Authorisation holder	CSL Behring GmbH
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	Beriplex® P/N
D.3.2	Product code	BE1116
D.3.4	Pharmaceutical form	Powder and solvent for solution for injection
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.1	CAS number	9001267
D.3.9.2	Current sponsor code	Human coagulation factor II
D.3.9.3	Other descriptive name	FACTOR II
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.3.9.1	CAS number	9001256
D.3.9.2	Current sponsor code	Human coagulation factor VII
D.3.9.3	Other descriptive name	FACTOR VII
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.3.9.1	CAS number	8000079756
D.3.9.2	Current sponsor code	Human coagulation factor IX
D.3.9.3	Other descriptive name	FACTOR IX
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.3.9.1	CAS number	9001290
D.3.9.2	Current sponsor code	Human coagulation factor X
D.3.9.3	Other descriptive name	FACTOR X
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.3.9.1	CAS number	8000050513
D.3.9.2	Current sponsor code	PROTEIN C
D.3.9.3	Other descriptive name	PROTEIN C
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.3.9.2	Current sponsor code	PROTEIN S
D.3.9.3	Other descriptive name	PROTEIN S
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	13 to 26
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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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	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	Plasma
D.3.4	Pharmaceutical form	Intravenous infusion
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PLASMA
D.3.9.1	CAS number	8000041078
D.3.9.2	Current sponsor code	Not Applicable
D.3.9.3	Other descriptive name	Not Applicable
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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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

Therapy of major bleeding resulting from an acquired deficiency of vitamin K-dependent coagulation factors and proteins C and S due to use of oral anticoagulation therapy

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	9.1
E.1.2	Level	LLT
E.1.2	Classification code	10009789
E.1.2	Term	Coagulation factors decreased

E.1.2 Medical condition or disease under investigation

E.1.2	Version	9.1
E.1.2	Level	LLT
E.1.2	Classification code	10005103
E.1.2	Term	Bleeding

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

PRIMARY OBJECTIVE:
To compare the hemostatic efficacy of Beriplex® P/N and plasma in ceasing spontaneous or traumatically-induced major bleeding in subjects who have a deficiency of vitamin K-dependent coagulation factors II, VII, IX, and X, as well as the proteins C and S, acquired from oral anticoagulation therapy.
CO-PRIMARY OBJECTIVE:
To compare the efficacy of Beriplex® P/N and plasma in rapidly reducing the international normalized ratio (INR, i.e. INR ≤ 3) values between the 2 treatment groups at 30 minutes after end of infusion.

E.2.2

Secondary objectives of the trial

· To compare the plasma levels of coagulation factors II, VII, IX, and X, protein C and S between the 2 treatment groups,
· To document the time from start of infusion until INR correction for both treatment groups,
· To document the time from randomization until INR correction for both treatment groups,
· To compare INR values between the 2 treatment groups at 30 minutes from the start of infusion
· To compare the use of non-study-prescribed blood products and/or hemostatic agents in both treatment groups,
· All-cause mortality at 45 days after treatment,
· To determine the safety and tolerability of Beriplex® P/N compared to that of plasma.
· To evaluate the neurological outcome as assessed by mRS for ICH subjects at day 45.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Male and female subjects ≥ 18 years,
• Subjects who have received anticoagulation therapy (warfarin,
acenocoumarol or phenprocoumon) ,
• Subjects who have acute major bleeding, defined as one of the
following:
o Life-threatening or potentially life-threatening,
o Acute bleeding associated with a fall in Hb level ≥
2g/dL,
o Bleeding requiring blood product transfusion (blood
products include plasma, red blood cells and other
coagulation factor products),
• INR ≥ 2 within 3 hours before start of study treatment,
• Informed consent has been obtained.

E.4

Principal exclusion criteria

• Expected survival of less than 3 days, or expected surgery٭ in
less than 1 day,
• Acute trauma for which reversal of vitamin K antagonists
alone would not be expected to control the acute bleeding
event,
• For patients with ICH:
o Glasgow coma score < 9,
o Intracerebral hematoma volume > 30cc as assessed by
ABC/21,
o For subdural hematomas: maximum thickness ≥ 10
mm, midline shift ≥ 5 mm,
o For subarachnoid hemorrhage: any evidence of
hydrocephalus,
o Infratentorial ICH location,
o Epidural hematomas,
o Intraventricular extension of hemorrhage,
o Modified Rankin score of >3 prior to ICH,
• History of thrombotic event, myocardial infarction,
disseminated intravascular coagulation, cerebral vascular
accident, transient ischemic attack, unstable angina pectoris,
or severe peripheral vascular disease within 3 months of
enrollment,
• Known history of antiphospholipid antibody syndrome or
lupus anticoagulant antibodies,
• Suspected or confirmed sepsis at time of enrollment,
• Administration of whole blood, plasma, plasma fractions or
platelets within 2 weeks prior to inclusion into the study
o Note: Administration of packed red blood cells is not
an exclusion criterion,
• Large blood vessel rupture (e.g. in advanced cancer patient),
• Pre-existing progressive fatal disease with a life expectancy of
less than 2 months,
• Known inhibitors to coagulation factors II, VII, IX, or X; or
hereditary protein C or protein S deficiency; or heparininduced,
type II thrombocytopenia,
• Treatment with any other investigational medicinal product
within 30 days prior to inclusion into the study,
• Presence or history of hypersensitivity to components of the
study medication,
• Pregnant or breast-feeding women,
• Prior inclusion in this study or any other CSL Behring
sponsored Beriplex study.
٭Subjects with acute major bleeding requiring minimal invasive
procedures (e.g. endoscopy, bronchoscopy, central lines) that are
indicated for diagnostic or therapeutic reasons are not excluded
per protocol, as long as plasma is intended to be given for
treatment of major bleeding.

E.5 End points

E.5.1

Primary end point(s)

Primary endpoint: Hemostatic efficacy
The primary efficacy variable will be the hemostatic efficacy over the period from start of infusion
until 24 hours after the start of infusion with respect to the adequacy of stopping an ongoing bleed. For hemostatic efficacy, the adequacy of cessation of a bleed will be rated by the DSMB (primary assessment) and the physician (secondary assessment) as excellent, good, or poor/none, based onpre-specified definitions. The hemostatic efficacy (DSMB and investigator’s classification of
clinical efficacy) will be described in frequency tables.
The primary analysis will be performed on the DSMB assessment in the ITT population.
A secondary analysis will be performed for the PP population.
Additional subgroup analyses by type of oral coagulation will be provided (ITT and PP).
The primary efficacy analysis in this study will be a test for the non-inferiority of the effect of
Beriplex® P/N compared to that of plasma on the binary hemostatic efficacy variable (a score
of “excellent” or “good” versus a score of “poor/none” as specified in Table 4 – Rating of
hemostatic efficacy).
If the above null hypothesis of inferiority can be rejected, Beriplex® P/N will also be tested for
superiority compared to plasma.

Co-primary endpoint: INR decrease
The co-primary endpoint will be the proportion of subjects who have a rapid decrease of INR,
defined as an INR value of 1.3 or less at 30 minutes after end of infusion.
The non-inferiority of the effect of Beriplex® P/N compared to that of plasma on the proportion
of subjects who have a rapid decrease of INR will be tested, if non-inferiority with regard to the
primary endpoint (hemostatic efficacy) is shown. The method to test for non-inferiority will be
the same as for hemostatic efficacy, including hypothesis, test procedure, maximum type I error,
and non-inferiority margin.
The course of INR will be shown graphically and descriptively by treatment group (mean, standard deviation (SD), median, quartiles, minimum, and maximum).

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

Yes

E.6.5

Efficacy

Yes

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)

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Fresh-frozen or 24-hour or thawed plasma that has been donor tested

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

Information not present in EudraCT

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

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 end of the study is defined as the date of the last visit (end of viral safety follow-up) of the last subject undergoing 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 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

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.1.3

Elderly (>=65 years)

Yes

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

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

Yes

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

176

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 needed

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

2009-01-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2009-01-16

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

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