Clinical Trials Register

Summary
EudraCT Number:	2008-001104-23
Sponsor's Protocol Code Number:	CSLCT-BIO-07-47
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:	2009-01-10
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

2008-001104-23

A.3

Full title of the trial

A Phase II, multicentre, double-blinded, randomised, cross-over
study to evaluate efficacy, safety and pharmacokinetics of
Biostate® in subjects with Haemophilia A.

A.4.1

Sponsor's protocol code number

CSLCT-BIO-07-47

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	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	Biostate [SP]
D.3.2	Product code	Biostate [SP]
D.3.4	Pharmaceutical form	Powder and solvent for solution for infusion
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Intravenous use Intravenous bolus use (Noncurrent)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.3	Other descriptive name	HUMAN COAGULATION FACTOR VIII
D.3.10	Strength
D.3.10.1	Concentration unit	IU international unit(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	500
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.3	Other descriptive name	von Willebrand Factor
D.3.10	Strength
D.3.10.1	Concentration unit	IU international unit(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1000
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	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	Biostate [RP]
D.3.2	Product code	Biostate [RP]
D.3.4	Pharmaceutical form	Powder and solvent for solution for infusion
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Intravenous use Intravenous bolus use (Noncurrent)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.3	Other descriptive name	HUMAN COAGULATION FACTOR VIII
D.3.10	Strength
D.3.10.1	Concentration unit	IU international unit(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	500
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.3	Other descriptive name	von Willebrand Factor
D.3.10	Strength
D.3.10.1	Concentration unit	IU international unit(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1000
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

Haemophilia A - a hereditary bleeding disorder characterised by a deficiency in the plasma protein known as coagulation Factor VIII (FVIII).

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	10018938
E.1.2	Term	Haemophilia A (Factor VIII)

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

1. To assess the efficacy of Biostate® [SP] in subjects with Haemophilia A

2. To assess the comparability of the pharmacokinetics of Biostate® [RP] and Biostate® [SP] in subjects with Haemophilia A

E.2.2

Secondary objectives of the trial

To assess the safety of Biostate® [SP] in subjects with Haemophilia A

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Subjects must meet all of the following inclusion criteria to be eligible to participate in this study:
1. Male subjects who are at least 12 years.
2. Subjects who have been diagnosed with Haemophilia A and have ≤ 1% FVIII levels in the absence of factor replacement according to their medical history.
3. Subjects with evidence of vaccination against hepatitis A and B (or presence of antibodies against hepatitis A and B due to either a previous infection or prior immunisation) within 10 years prior to Day 1 documented in the medical notes.
4. Subjects with at least 150 prior exposure days to a FVIII replacement product
confirmed by their treating physician.
5. Subjects and/or their legally acceptable representatives who understand the
nature of the study, and have given written informed consent to participate in the
study.

E.4

Principal exclusion criteria

Subjects who fulfil the following criteria will not ´be eligible for inclusion into this trial:

For participation in the PK part:
1. Subjects who are actively bleeding.
2. Subjects with body weight > 100 kg

For all subjects at Day 1:

3. Subjects who have received an infusion of any FVIII product, cryoprecipitate, whole blood, plasma, or DDAVP in the 4 days prior to Day 1.
4. Subjects with a known history of FVIII inhibitors, or have a FVIII inhibitor
level of > 0.6 Bethesda Units (BU) at screening.
5. Subjects who have received aspirin or other Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) within 7 days of administration of study product.
6. Subjects with CD4 lymphocytes < 200/µL (in their medical history and/or at screening if available results are older than one year). Subjects that are HIV-1 positive may be considered for the study if viral load ≤ 200 particles/µL at screening, and all other eligibility criteria are met.
7. Subjects with impaired liver function ie. bilirubin >1.5 x upper limit of normal (ULN) and/or AST/ALT >2.5 x ULN (referring to limits of the laboratory that performs the determination) at screening.
8. Subjects suffering an acute or chronic medical condition, other than haemophilia A, which may, in the opinion of the Investigator, affect the conduct of the study.
9. Subjects suffering von Willebrand Disease with vWF:RCo level < 50 IU/dL at screening
10. Subjects having evidence or a history (within the previous 12 months) of abuse of any drug substance, licit or illicit.
11. Subjects with a known or suspected hypersensitivity or previous evidence of severe side effects to Biostate®, FVIII concentrates or human albumin.
12. Subjects who have participated in a clinical study or used an investigational compound (e.g. a new chemical entity not approved for clinical use) in the three months preceding the first day of study drug administration, or who are planning to enter such a study during the study period.
13. Subjects who are not willing and/or not able to comply with the study requirements.

E.5 End points

E.5.1

Primary end point(s)

Primary efficacy endpoint assessed during Part Two of the study. Thís awill include the following:
- Assessment of haemostatic efficacy by the Investigator using the grading scale of Excellent, Good, Moderate, None and will be evaluated on a retrospective monthly basis,
- Any blood product transfusion requirements, and the number of treatments/units required to resolve the event
- FVIII levels concentrate usage: number of infusions, IU/kg per event, month and per year.
- Assessment of blood loss during any surgical event

FVIII levels will be assessed to determine the minimum pharmacokinetic
parameters as follows:
1. Incremental recovery
2. Half life (T1/2)
3. Area under the concentration-time curve (AUC)
4. Mean residence time (MRT)
5. Volume of distribution at steady state (Vss)
6. Maximum plasma concentration (Cmax)
7. Time the maximum concentration occurs (Tmax)
8. Minimum plasma concentration (Cmin)
9. Total clearance of the drug from the body (CL = dose/AUC)

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

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

Yes

E.7.1.3.1

Other trial type description

Part One and Three: Comparability of the pharmacokinetics of Biostate [SP] and Biostate [RP]

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

Yes

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Note: This description pertains only to Part I of the study; Part II and Part III are open-label

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

Yes

E.8.2.3.1

Comparator description

Note: This pertains to Part I only. Part II and Part III of the trial do not have a comparator

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.8.5

The trial involves multiple Member States

Yes

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

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.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	No
F.1.1.6	Adolescents (12-17 years)	Yes
F.1.2	Adults (18-64 years)	Yes
F.1.3	Elderly (>=65 years)	No
F.2 Gender
F.2.1	Female	No
F.2.2	Male	Yes
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	No
F.3.3.1	Women of childbearing potential not using contraception	No
F.3.3.2	Women of child-bearing potential using contraception	No
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	55
F.4.2	For a multinational trial
F.4.2.1	In the EEA	65
F.4.2.2	In the whole clinical trial	80

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

2009-01-22

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2010-10-15

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