Clinical Trials Register

Summary
EudraCT Number:	2011-004154-25
Sponsor's Protocol Code Number:	984
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:	2018-11-07
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

2011-004154-25

A.3

Full title of the trial

A prospective, open-label, phase I/III study investigating pharmacokinetic properties of BT524 and efficacy and safety of BT524 in the treatment and prophylaxis of bleeding in patients with congenital fibrinogen deficiency

Проспективно, открито, фаза I/III изпитване, изследващо
фармакокинетичните свойства на BT524 и ефикасността и
безопасността на BT524 при лечение и профилактика на кървене при
пациенти с вроден дефицит на фибриноген

A.3.1

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

Clinical study investigating pharmacokinetic properties of BT524 and efficacy and safety of BT524 in the treatment and prophylaxis of bleeding in patients with congenital fibrinogen deficiency

A.4.1

Sponsor's protocol code number

984

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/285/2018

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Biotest AG
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	Biotest AG
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	Biotest AG
B.5.2	Functional name of contact point	Corporate Clinical Research
B.5.3	Address:
B.5.3.1	Street Address	Landsteinerstraße 5
B.5.3.2	Town/ city	Dreieich
B.5.3.3	Post code	63303
B.5.3.4	Country	Germany
B.5.4	Telephone number	4961038014941
B.5.5	Fax number	496103801341
B.5.6	E-mail	Claudia.Schulte@biotest.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	Fibrinogen Concentrate from Human Plasma
D.3.2	Product code	BT524
D.3.4	Pharmaceutical form	Powder for solution for injection/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	Human Fibrinogen Concentrate
D.3.9.1	CAS number	9001-32-5
D.3.9.2	Current sponsor code	BT524
D.3.9.3	Other descriptive name	Human Fibrinogen Concentrate
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	14 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.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

Patients with congenital afibrinogenemia or severe congenital hypofibrinogenemia

E.1.1.1

Medical condition in easily understood language

Inherited fibrinogen deficiency.

E.1.1.2

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

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	10066356
E.1.2	Term	Congenital hypofibrinogenaemia
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

To investigate the 14 day single-dose pharmacokinetics of BT524 following intravenous infusion in patients with congenital fibrinogen deficiency (afibrinogenemia or severe hypofibrinogenemia).

E.2.2

Secondary objectives of the trial

To investigate the 14 day single-dose pharmacodynamics, the surrogate efficacy and safety of the single intravenous infusion of BT524.
To investigate efficacy, surrogate efficacy and safety, of single and/or repetitive intravenous infusions of BT524 for on-demand prophylaxis (ODP) and/or on-demand treatment (ODT) of bleeding events.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Known congenital afibrinogenemia or severe congenital hypofibrinogenemia
2. Plasma fibrinogen activity ≤ 0.5 g/l and antigen ≤ 0.5 g/l
3. Male or female
4. Age 0 to 75 years, with the first ten patients will be 18 years or older
5. Presumed to be compliant with the study procedures and to terminate the study as scheduled
6. Willing and able to be hospitalized for 3 days for the pharmaco-kinetic assessment (if applicable)
7. Willing and able to be hospitalized - if required - in case of interventions (e.g., surgical procedures, major bleeds)
8. Written informed consent by the patient, his/her parents or by the patient's legal / authorized representative as applicable

E.4

Principal exclusion criteria

General exclusion criteria:
1. Known congenital dysfibrinogenemia
2. Known bleeding disorder other than congenital fibrinogen deficiency
3. History of esophageal variceal bleeding
4. Known presence or history of venous/arterial thrombosis or thromboembolic event (TEE) in the preceding 6 months
5. Known presence or history of fibrinogen inhibitory antibodies
6. Known presence or history of hypersensitivity to human fibrinogen or human plasma proteins e.g., immunoglobulins, vaccines or hypersensitivity to any of the excipients
7. Known positive serology for HIV-1 and HIV-2
8. Clinically relevant biochemical or hematological findings (except due to underlying disease or emergency bleeding) outside the normal range (at the investigator's discretion)
9. Clinically relevant pathological findings in physical examination including electrocardiogram (ECG)
10. Treatment with any fibrinogen concentrate and/or fibrinogen-containing product within 2 weeks prior to infusion of BT524
11. Concomitant medication interacting relevantly with the coagulation system (e.g., low molecular weight heparin, unfractioned heparin, factor Xa inhibitors, factor IIa inhibitors or PY12 inhibitors) within 2 weeks prior to infusion of BT524
12. Recent vaccination within 3 weeks prior to infusion*
13. Body weight (BW) below 22 kg for patients ≥ 6 years*; BW below the 5th percentile of the normal range for children **
14. End stage disease
15. Abuse of drugs
16. Unable to understand and follow the study requirements (refers to the patient, his/her parents or to the patient's legal / authorized representative as applicable)
17. Participation in another interventional clinical study within 30 days before entering the study or during the study
18. Pregnant/ nursing woman, or woman of childbearing potential not using reliable/ effective contraceptive method(s) during the study and at least one month after the last administration of study drug (e.g., oral/ injectable/ implantable/ insertable/ topical hormonal contraceptives, intrauterine devices, female sterilization, partner's vasectomy or condoms)
19. Any other condition that, to the investigator's judgment, could have an impact on patient's safety or the study results
* only applicable for patients in PK part I
** refers to local standards

PK-specific exclusion criteria:
20. Elective surgery during the 14 day PK blood sampling period
21. Acute infection
22. Clinically relevant increase or decrease in body temperature
23. Actively bleeding or anticipated bleeding (including female menorrhea) at the time point of or within 7 days prior to infusion of BT524
24. Surgery within 7 days prior to infusion of BT524
25. Immobilization within 7 days prior to infusion of BT524
26. Intake of alcohol or significantly increased intake of caffeine containing products within 24 hours prior to infusion of BT524
27. Blood donation or comparable blood loss within 60 days prior to infusion of BT524
28. Excessive physical exercise (extreme sports activities, sauna) within 72 hours prior to infusion of BT524

E.5 End points

E.5.1

Primary end point(s)

Pharmacokinetics
Single-dose pharmacokinetics of fibrinogen antigen will be assessed by the following variables:
• Terminal Elimination Half-life (t1/2) for fibrinogen antigen
• Time to reach Maximum Concentration (tmax)
• Maximum Concentration (Cmax)
• Area Under the Concentration-Time Curve (AUC) calculated to the last measured concentration (AUC(0-t)) and extrapolated to infinity (AUC(0-inf)
• Clearance (CL)
• Mean Residence Time (MRT)
• Volume of Distribution (Vss)
• Incremental Recovery (IR)
• Classical in vivo Recovery (IVR)

E.5.1.1

Timepoint(s) of evaluation of this end point

After a single intravenous infusion pharmacokinetics will be assessed for 14 days.

E.5.2

Secondary end point(s)

-Pharmacodynamics: Single-dose pharmacodynamics of fibrinogen activity will be assessed
-Surrogate Efficacy: Maximum clot firmness (MCF, mm)
-Clinical Efficacy
-Safety

E.5.2.1

Timepoint(s) of evaluation of this end point

After a single intravenous infusion pharmacodynamics will be assessed for 14 days.
Total duration of individual study participation in both study parts is at least 15 months.
For patients included only in part II of the study individual study participation will be at least 12 months.

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

Yes

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)

Yes

E.7.1.1

First administration to humans

Yes

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)

Yes

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

E.8.1.1

Randomised

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

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

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

Bulgaria

Germany

Lebanon

Tunisia

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

Last visit of the last subject.

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

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:

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)

Yes

F.1.1.4.1

Number of subjects for this age range:

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

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

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Male and female patients from birth to less than 18 years of age with congenital fibrinogen deficiency

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

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)

None.

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

2019-01-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-03-12

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2020-05-15

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