Clinical Trials Register

Summary
EudraCT Number:	2012-002554-23
Sponsor's Protocol Code Number:	GENA-05
National Competent Authority:	Slovenia - JAZMP
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-12-08
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

Slovenia - JAZMP

A.2

EudraCT number

2012-002554-23

A.3

Full title of the trial

Immunogenicity, Efficacy and Safety of Treatment with Human-cl rhFVIII in Previously Untreated Patients with Severe Haemophilia A

A.3.1

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

The ability to induce an immune response, efficacy and safety of treatment with Human-cl rhFVIII in previously Untreated Patients ,affected by inherited gender-related coagulation disorder ,in which affected males do not produce functional coagulation factor VIII (FVIII) in sufficient quantities to achieve satisfactory blood clotting.

A.4.1

Sponsor's protocol code number

GENA-05

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/92/2011

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	OCTAPHARMA AG
B.1.3.4	Country	Switzerland
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	OCTAPHARMA AG
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	InVentiv Health Clinical UK Ltd
B.5.2	Functional name of contact point	Regulatory Affairs
B.5.3	Address:
B.5.3.1	Street Address	Thames House, 17-19 Marlow Road, Maidenhead,
B.5.3.2	Town/ city	Maidenhead, berkshire
B.5.3.3	Post code	SL6 7AA
B.5.3.4	Country	United Kingdom
B.5.6	E-mail	Regopseurope@inventivhealth.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	Human cell line recombinant factor VIII
D.3.2	Product code	Human-cl rhFVIII
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	Human-cl rhFVIII
D.3.9.1	CAS number	N.A
D.3.9.2	Current sponsor code	140
D.3.9.3	Other descriptive name	Human Coagulation Factor VIII
D.3.9.4	EV Substance Code	SUB13815MIG
D.3.10	Strength
D.3.10.1	Concentration unit	IU international unit(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	250 to 2000
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	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
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	Yes
D.3.11.13.1	Other medicinal product type	Replacement therapy for deficiency of coagulation factor VIII

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

Severe Haemophilia A

E.1.1.1

Medical condition in easily understood language

An inherited gender-related coagulation disorder in which affected males do not produce functional coagulation factor VIII (FVIII) in sufficient quantities to achieve satisfactory blood clotting.

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	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10018938
E.1.2	Term	Haemophilia A (Factor VIII)
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 immunogenicity of Human-cl rhFVIII in 100 PUPs suffering from severe haemophilia A (FVIII:C < 1%).

E.2.2

Secondary objectives of the trial

• To assess the efficacy of Human-cl rhFVIII during prophylactic treatment (based on the frequency of spontaneous break-through bleeds)
• To assess the efficacy of Human-cl rhFVIII during treatment of bleeds
• To assess the efficacy of Human-cl rhFVIII in surgical prophylaxis
• To assess the safety and tolerability of Human-cl rhFVIII

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

1.Recovery investigation (optional);
A recovery investigation is recommended to be performed with the first Human-cl rhFVIII administration, or within the first three months after treatment start with Human-cl rhFVIII, in any case in a non-bleeding patient. A dose of 40 IU FVIII/kg BW will be administered and the in vivo recovery will be calculated from the FVIII levels before infusion and the peak level obtained from the 15 min and 1 hour post-infusion samples. Recovery investigations are recommended to be repeated
approximately every 6 months.
2.RNA Expression.
RNA expression analysis will optionally be performed in order to provide an understanding of the transcript activity of the genes involved in immune responses that may be responsible for FVIII inhibitor formation in patients receiving exogenous FVIII. RNA expression analysis will also be optionally performed on patients undergoing ITI to provide information on the transcript activity of genes involved in immune tolerance. The analysis will be carried out using a customised PAXgene
protocol in which RNA samples will be obtained by using commercially available PAXgene RNA blood collection tubes and customised microfuge tubes. This customised approach has previously been used in both a paediatric and animal study where samples volumes are limited.
3.Immunogenotyping (Partly Optional);
Immunogenotyping will be performed in order to investigate genetic factors that might influence development of FVIII inhibitors. It will include analysis of FVIII gene mutations, HLA-typing, immune response gene profiling and FVIII ethnic haplotype analysis. FVIII mutation analysis is a required assessment, whereas HLA-typing, immune response gene profiling and FVIII ethnic haplotype are optional. Blood samples required for this analysis can be obtained at any time during study, but it is recommended that they be obtained at the same time as the samples for scheduled study visits.
4.In vitro immunogenicity of FVIII products (optional).
Immunogenicity of Human-cl rhFVIII will be assessed by culturing peripheral blood monocyte cells (PBMC) from the patients (including a positive control) with Human-cl rhFVIII. The nature of T cell response will be assessed by analysing cytokine expression (measured in a multiplex format) and T cell proliferation. Cytokines analysed will include IL-2, TNFα, IFNγ, IL-5, IL-6, IL-10, and IL-17 (TGFβ may also included in an ELISA format).
5.Epitope mapping in case of inhibitor development;

E.3

Principal inclusion criteria

In order to qualify for study enrolment, the following criteria must be fulfilled before study entry:
1. Male patients
2. Severe haemophilia A (FVIII:C < 1%)
3. No previous treatment with FVIII concentrates or other blood products containing FVIII
4. Voluntarily given, fully informed written and signed consent given before any study related procedures are conducted (obtained from the patient’s parent(s)/legal guardian(s))

E.4

Principal exclusion criteria

Patients will not be included if any of the following exclusion criteria are met:
1. Diagnosis of a coagulation disorder other than haemophilia A
2. Severe liver or kidney disease (ALT or AST levels >5 times of upper limit of normal (ULN), creatinine >120 μmol/L)
3. Concomitant treatment with any systemic immunosuppressive drug
4. Participation in another interventional clinical study currently or during the past
4 weeks

E.5 End points

E.5.1

Primary end point(s)

Immunogenicity of Human-cl rhFVIII is the primary endpoint. Inhibitor activity will be determined by the modified Bethesda assay (Nijmegen modification), using congenital FVIIIdeficient human plasma, spiked with Human-cl rhFVIII. In case of a positive inhibitor result, an inhibitor retesting, using a second separately drawn sample, should be performed. A FVIII inhibitor is defined as “positive”, if the retesting confirms the positive result, otherwise the result is considered as being “negative”.

E.5.1.1

Timepoint(s) of evaluation of this end point

• At baseline (Screening Visit)
• Every 3-4 EDs until ED 20
• Every 10-12 EDs or every 3 months ± 2 weeks (whichever comes first) after ED 20 until 100 EDs are reached
• Any time in the case of suspicion of an inhibitor development

E.5.2

Secondary end point(s)

1)Efficacy
a) Efficacy of prophylactic treatment
The efficacy of Human-cl rhFVIII in the prophylactic treatment will be investigated by calculating the frequency of spontaneous break-through bleeds under prophylactic treatment.
Study drug consumption data (FVIII IU/kg per month, per year) per patient and in total will be evaluated. The dates and times of study drug infusions, the details of dose(s), and the product batch numbers used for the prophylactic treatment will be documented.
b) Efficacy of treatment of bleeds
The efficacy of Human-cl rhFVIII in the treatment of bleeds will be investigated by using a 4-point ordinal haemostatic efficacy scale. Details of the bleed, the amount of Human-cl rhFVIII needed and the number of injections necessary to stop the bleed will be documented.
c) Efficacy of surgical prophylaxis
In surgical procedures, the following parameters will be documented:
• Overall efficacy assessment (taking into account the intra- and post-operative assessment) after the end of surgical prophylactic treatment phase, performed by the surgeon and by the haematologist.
• Average and maximum expected estimated blood loss, compared to the actual estimated blood loss.
• Details on surgical procedure: location, severity, type, expected and actual duration
• Pre-, intra-, and post-operative FVIII plasma levels, if appropriate
• Details of administered dose(s) of Human-cl rhFVIII given pre-, intra- and/or postoperatively including dates, times and batch numbers
• Details on concomitantly administered drugs, including all blood and blood product
transfusions, excluding standard anaesthetic drugs
• Details on all wound haematomas in terms of capturing, analysing, and reporting these, including any need for surgical evacuation
• Outcome of the intervention, described by means of a brief narrative
2.Safety
Safety and tolerability will be assessed by monitoring vital signs, standard laboratory parameters, and by monitoring adverse events (AEs).

E.5.2.1

Timepoint(s) of evaluation of this end point

1)Efficacy
In the prevention and the treatment of bleeds, the frequency of break-through bleeds in case of prophylactic treatment, the efficacy in surgical prophylaxis of Human-cl rhFVIII will be thoroughly assessed. In the course of the follow-up visits (i.e. every 3-4 EDs until ED 20, then every 10-12 EDs until ED 100), scheduled to be performed after the Screening Visit, FVIII inhibitor levels will be assessed.
These visits may be combined with the additional regular 3 monthly (± 2 weeks) follow-up visits.
2) Safety
AEs and changes in concomitant medication, overall safety and tolerability will be checked and documented at each follow-up visit.

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

Yes

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

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.8.2.4

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

Brazil

Canada

Colombia

Croatia

France

Georgia

Germany

India

Moldova, Republic of

Poland

Portugal

Russian Federation

Slovenia

Spain

Ukraine

United Kingdom

United States

Venezuela, Bolivarian Republic of

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

LVLS

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

Yes

F.1.1

Number of subjects for this age range:

100

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)

Yes

F.1.1.3.1

Number of subjects for this age range:

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)

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

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

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

children

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

100

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
G.4 Investigator Network to be involved in the Trial: 1

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2015-02-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-02-16

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2020-03-24

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