Clinical Trials Register

Summary
EudraCT Number:	2007-007862-39
Sponsor's Protocol Code Number:	BE1116_3003
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

2007-007862-39

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 vitamin K antagonists in subjects requiring an urgent surgical procedure

Отворено, рандомизирано, многоцентрово, фаза IIIB проучване за оценка на ефикасността, безопасността и поносимостта на Beriplex® P/N сравнен с плазма за бърза обратимост на коагулопатия, индуцирана от антагонисти на витамин К при участници, изискващи спешна хирургична процедура

A.3.1

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

A study to assess the efficacy of Beriplex P/N compared with plasma for quick reversal of anticoagulant medicines in patients who require an urgent surgery

Проучване за оценка на ефикасността на Beriplex P/N в сравнение с плазма, за бързо обратно повлияване, след прием на антикоагулантни лекарства при пациенти, които се нуждаят от спешна операция

A.4.1

Sponsor's protocol code number

BE1116_3003

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT00803101

A.5.4

Other Identifiers

Name:

IND number

Number:

13398

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	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	CSL Behring GmbH
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	Worldwide Clinical Trials
B.5.2	Functional name of contact point	PROGRAM DIRECTOR
B.5.3	Address:
B.5.3.1	Street Address	14, 13th LINE V.O.
B.5.3.2	Town/ city	ST. PETERSBURG
B.5.3.3	Post code	199034
B.5.3.4	Country	Russian Federation
B.5.4	Telephone number	+7 81232771082221
B.5.5	Fax number	+7 8123468248
B.5.6	E-mail	Yuri.Kabanov@wwctrials.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	Yes
D.2.1.1.1	Trade name	Beriplex P/N 500
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.3.4	Pharmaceutical form	Powder and solvent for solution for injection
D.3.4.1	Specific paediatric formulation	No
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	FACTOR II
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.3.8	INN - Proposed INN	FACTOR VII
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.3.8	INN - Proposed INN	FACTOR IX
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.3.8	INN - Proposed INN	FACTOR X
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.3.8	INN - Proposed INN	PROTEIN C
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.3.8	INN - Proposed INN	PROTEIN S
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)	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.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	Blood plasma
D.3.2	Product code	Not applicable
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
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.3.10	Strength
D.3.10.1	Concentration unit	ml millilitre(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	400 to 1500
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

Perioperative prophylaxis for emergency surgery in subjects who have an acquired deficiency of vitamin K-dependent coagulation factors and proteins C and S

Периоперативна профилактика за спешна операция при пациенти, които имат придобит дефицит на витамин К-зависимите фактори на кръвосъсирването и протеините C и S

E.1.1.1

Medical condition in easily understood language

Patients under anticoagulant therapy requiring an urgent surgical procedure
(Reversal of Coagulopathy)

Пациенти на антикоагулантна терапия, нуждаещи се от спешна хирургична процедура
(Обръщане на коагулопатия)

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	14.1
E.1.2	Level	PT
E.1.2	Classification code	10065667
E.1.2	Term	Haemorrhage prophylaxis
E.1.2	System Organ Class	10042613 - Surgical and medical procedures

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10009789
E.1.2	Term	Coagulation factors decreased
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

To compare the hemostatic efficacy of Beriplex® P/N and plasma preventing excessive hemorrhages during emergency surgical interventions in subjects who have a deficiency of vitamin K-dependent coagulation factors II, VII, IX, X and proteins C and S acquired from oral anticoagulation.
CO-PRIMARY OBJECTIVE:
To compare efficacy of Beriplex® P/N and plasma in rapidly reducing pre-operative international normalized ratio (INR) values between the 2 treatment groups at 30 minutes after end of infusion.

Да се сравни хемостазната ефикасност на Beriplex ® P/N и плазма за предотвратяване на обилни кръвоизливи по време на спешни хирургични интервенции при пациенти, които имат дефицит на витамин К-зависимите коагулационни фактори II, VII, IX, X и протеини С и S, придобит от перорална антикоагулантна терапия.
Допълнителна основна цел:
Да се сравни ефикасността на Beriplex ® P / N и плазма за бързо преоперативно намаляване на INR стойности между 2-те групи на лечение на 30 минути след края на инфузията.

E.2.2

Secondary objectives of the trial

• To compare the plasma levels of coagulation factors II, VII, IX, and X, and protein C, and protein S between both treatment groups,
• To compare the time from start of infusion until INR correction for both treatment groups,
• To compare the total number of red blood cell (PRBC and whole blood) transfusions and the proportion of subjects receiving 1 or more transfusions between both treatment groups from the start of the urgent surgical procedure to 24 hours from the start of the urgent surgical procedure

• Да се сравнят плазмените нива на коагулационни фактори II, VII, IX и X, както и протеин С и протеин S между двете терапевтични групи,
• Да се сравни времето от началото на инфузията до корекцията на INR за двете терапевтични групи,
• Да се сравни общият брой трансфузии на червените кръвни клетки (PRBC и цяла кръв) и дялът на пациентите, получаващи едно или повече кръвопреливания между двете терапевтични групи от началото на спешната хирургична процедура до 24 часа от началото на спешната хирургична процедура

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

. Male and female subjects 18 years or more,
. Subjects currently on oral VKA therapy,
. An urgent surgical procedure is required within 24 hours of the start of IMP,
. Due to the nature of the procedure, withdrawal of oral VKA therapy and infusion of plasma are also indicated to reverse the VKA effect,
. INR . 2 within 3 hours before start of IMP,
. Informed consent has been obtained.

. Мъже и жени на 18 години или повече,
. Пациенти на перорална VKA терапия в момента,
. Необходимост от спешна хирургична процедура в рамките на 24 часа от началото на инфузията,
. Поради естеството на процедурата, е необходимо спиране на пероралната VKA терапия и инфузия на плазма за обръщане ефекта на VKA,
. INR 2 в рамките на 3 часа преди началото на инфузията,
. Подписано информирано съгласие.

E.4

Principal exclusion criteria

• Subjects requiring urgent surgical procedures where according to the surgeon's clinical judgment, an accurate estimate of blood loss is not possible (e.g., ruptured aneurysm)
• Subjects in whom lowering INR within normal range may present an unacceptable risk for a thromboembolic complication where the INR goal is to lower but not normalize the INR because of risk of a procedure-associated stroke
• Acute trauma for which reversal of vitamin K antagonists alone would not be expected to control or resolve an acute bleeding complication and/or control the acute bleeding event
• History of thromboembolic event, myocardial infarction, unstable angina pectoris, critical aortic stenosis, cerebral vascular accident, transient ischemic attack, severe peripheral vascular disease, disseminated intravascular coagulation within 3 months of enrollment

• Пациенти, нуждаещи се от спешни хирургични процедури, където според клиничната преценка на хирурга, точна оценка на очакваната кръвозагуба не е възможна (напр., разкъсанa аневризма)
• Пациенти, при които понижаване на INR в нормални граници може да представлява неприемлив риск за тромбоемболични усложнения, където се цели да се намали INR, но не и да се нормализира, поради риск от свързан с процедурата инсулт
• Остра травма при която, обръщането на ефекта на антагонистите на витамин К самостоятелно не може да контролира или да предотврати остро усложнение при кървене и / или да контролира остър кръвоизлив
• История на тромбоемболични събития, миокарден инфаркт, нестабилна стенокардия, критична аортна стеноза, мозъчен съдов инцидент, транзиторни исхемични атаки, тежка периферна съдова болест, дисеминирана вътресъдова коагулация в рамките на 3 месеца преди включване в изпитването

E.5 End points

E.5.1

Primary end point(s)

1) Hemostatic efficacy in preventing excessive hemorrhages during emergency surgical interventions
2) Proportion of subjects who have a rapid decrease of INR, defined as an INR value of 1.3 or less

1) Ефикасност на хемостазата за предотвратяване на обилни кръвоизливи по време на спешни хирургични интервенции
2) Дял от пациентите, които са имали бързо намаление на INR, намаляне до стойности на INR от 1,3 или по-малко

E.5.1.1

Timepoint(s) of evaluation of this end point

1) Start of infusion until immediately after surgery
2) Baseline vs. 30 minutes after end of infusion

1) Стартиране на инфузията, до веднага след операцията
2) Начало срещу 30 минути след края на инфузията

E.5.2

Secondary end point(s)

• Time to INR correction (INR ≤ 1.3) from start of infusion of IMP,
• Number of units of red blood cells (PRBCs and whole blood) from the start of surgery through 24 hours from the start of surgery,
• Proportion of subjects receiving red blood cells (PRBCs and whole blood) from the start of surgery through 24 hours from the start of surgery,
• Plasma levels of Factors II, VII, IX, X and Proteins C and S

• Време за корекция на INR (INR ≤ 1,3) от началото на инфузията на ИМП,
• Брой трансферирани единици с червените кръвни клетки (PRBCs и цяла кръв) от началото на операцията до 24 часа от началото на операцията,
• Дял на лицата, получаващи червени кръвни клетки (PRBCs и цяла кръв) от началото на операцията до 24 часа от началото на операцията,
• Плазмени нива на факторите II, VII, IX, X и протеини C и S

E.5.2.1

Timepoint(s) of evaluation of this end point

Secondary endpoints 1 to 3:
Start of surgery to 24 hours after end of surgery
Secondary endpoint 4
Pre-infusion through 3 hours after administration

Вторични крайни точки от 1 до 3:
Начало на операцията до 24 часа след края на операцията
Вторична крайна точка 4
Преди инфузия до 3 часа след приложението

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

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

Прясно замразена или размразена за 24-часa плазма, която е била донор тествана

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

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

Belarus

Bulgaria

Italy

Lebanon

Romania

Russian Federation

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 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.

Края на изпитването се определя като датата на последното посещение на последния пациент в изпитването (края на проследяването за вирусна безопасност).

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

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

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
P.	Date of the global end of the trial	2013-02-22

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