Clinical Trials Register

Summary
EudraCT Number:	2015-002136-40
Sponsor's Protocol Code Number:	261203
National Competent Authority:	Austria - BASG
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-01-29
Trial 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

Austria - BASG

A.2

EudraCT number

2015-002136-40

A.3

Full title of the trial

Phase 3, prospective, multi-center, open label study to investigate safety, immunogenicity, and hemostatic efficacy of PEGylated Factor VIII (BAX 855) in previously untreated patients (PUPs) < 6 years with severe hemophilia A (FVIII < 1%)

A.3.1

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

A study of safety, effect on the immune system and blood clotting of BAX855 (factor VIII of blood clotting) in pediatric patients who have not received treatment for their severe hemophilia A.

A.3.2

Name or abbreviated title of the trial where available

BAX855 PUP study

A.4.1

Sponsor's protocol code number

261203

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/072/2013

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Baxalta Innovations GmbH
B.1.3.4	Country	Austria
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	Baxalta Innovations GmbH
B.4.2	Country	Austria
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Baxalta US Inc
B.5.2	Functional name of contact point	Archana Savla
B.5.3	Address:
B.5.3.1	Street Address	650 East Kendall Street 5th Floor
B.5.3.2	Town/ city	Cambridge, MA
B.5.3.3	Post code	02142
B.5.3.4	Country	United States
B.5.4	Telephone number	+1617 588 8208
B.5.6	E-mail	archana.salva@baxalta.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	PEGylated rFVIII
D.3.2	Product code	BAX855
D.3.4	Pharmaceutical form	Powder and solution 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	Not applicable
D.3.9.2	Current sponsor code	BAX855
D.3.9.3	Other descriptive name	BAX 855 (PEGYLATED RFVIII)
D.3.9.4	EV Substance Code	SUB90763
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	250
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Not applicable
D.3.9.2	Current sponsor code	BAX 855
D.3.9.3	Other descriptive name	BAX 855 (PEGYLATED RFVIII)
D.3.9.4	EV Substance Code	SUB90763
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.3.8	INN - Proposed INN	Not applicable
D.3.9.2	Current sponsor code	BAX 855
D.3.9.3	Other descriptive name	BAX 855 (PEGYLATED RFVIII)
D.3.9.4	EV Substance Code	SUB90763
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Not applicable
D.3.9.2	Current sponsor code	BAX 855
D.3.9.3	Other descriptive name	BAX 855 (PEGYLATED RFVIII)
D.3.9.4	EV Substance Code	SUB90763
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	2000
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	not applicable
D.3.9.2	Current sponsor code	BAX855
D.3.9.3	Other descriptive name	BAX 855 (PEGYLATED RFVIII)
D.3.9.4	EV Substance Code	SUB90763
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	750
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	not applicable
D.3.9.2	Current sponsor code	BAX855
D.3.9.3	Other descriptive name	BAX 855 (PEGYLATED RFVIII)
D.3.9.4	EV Substance Code	SUB90763
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	1500
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Not applicable
D.3.9.2	Current sponsor code	BAX855
D.3.9.3	Other descriptive name	BAX 855 (PEGYLATED RFVIII)
D.3.9.4	EV Substance Code	SUB90763
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	3000
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	Recombinant product with covalently bound polyethyleneglycol

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 hemophilia A (FVIII <1%)

E.1.1.1

Medical condition in easily understood language

Hemophilia A

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	10060612
E.1.2	Term	Hemophilia A
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 determine safety including immunogenicity of BAX 855 based on the
incidence of inhibitor development to FVIII (≥ 0.6 BU/mL using the Nijmegen modification of the Bethesda assay)

E.2.2

Secondary objectives of the trial

Safety
1. To determine the immunogenicity of BAX 855 in terms of binding IgG and IGM antibodies to FVIII, PEG-FVIII and PEG
2. To determine the safety of BAX 855 based on adverse events (AEs) and serious adverse events (SAEs)
Hemostatic Efficacy
3. To assess the efficacy of prophylactic treatment with BAX 855
4. To characterize the efficacy of BAX 855 in the control of bleeding episodes
Pharmacokinetics
6. To determine the incremental recovery (IR) of BAX 855 at baseline and over time
7. To determine half-life of BAX 855 at baseline (optional)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Subject is < 6 years old at the time of screening
2. Subject is previously untreated with <3 EDs to ADVATE, BAX 855 or fresh frozen plasma (FFP) at any time prior to screening
3. Subject has severe hemophilia A (FVIII < 1%) as determined by the central laboratory, or a historical FVIII level < 1% as determined at any local laboratory and an optional additional FVIII gene mutation consistent with severe hemophilia A
4. Subject is immune competent with a CD4+ count > 200 cells/mm3, as confirmed by central laboratory at screening
5. Parent or legally authorized representative is willing and able to comply with the requirements of the protocol

E.4

Principal exclusion criteria

1. Subject has detectable FVIII inhibitory antibodies (≥ 0.6 BU using the Nijmegen modification of the Bethesda assay) as confirmed by central laboratory at screening
2. Subject has a history of FVIII inhibitory antibodies (≥ 0.6 BU using the Nijmegen modification of the Bethesda assay or the Bethesda assay) at any time prior to
screening
3. Subject has been diagnosed with an inherited or acquired hemostatic defect other than hemophilia A (eg, qualitative platelet defect or von Willebrand’s disease)
4. Subject has been previously treated with cryoprecipitate or any type of FVIII concentrate other than ADVATE or BAX 855, or was administered ADVATE or BAX 855 for ≥ 3 EDs at any time prior to screening
5. Subject has received any kind of blood-transfusion such as packed red blood cells (PRBC), platelets or plasma at any time prior to screening
6. The subject’s weight is < 5 kg (If a subject is close to weighing 5 kg at screening and will have reached a weight of at least 5 kg at the baseline visit, the subject is eligible for participation.)
7. Subject’s platelet count is < 100,000/mL
8. Subject has known hypersensitivity towards mouse or hamster proteins, PEG or Tween 80
9. Subject has severe chronic hepatic dysfunction [eg, > 5 times upper limit of normal alanine aminotransferase (ALT), aspartate aminotransferase (AST), or a documented INR > 1.5] in his medical history or at the time of screening
10. Subject has severe renal impairment (serum creatinine > 1.5 times the upper limit of normal)
11. Subject has current or recent (< 30 days) use of other PEGylated drugs prior to study participation or is scheduled to use such drugs during study participation
12. Subject is scheduled to receive during the course of the study a systemic immunomodulating drug (e.g. corticosteroid agents at a dose equivalent to
hydrocortisone greater than 10 mg/day, or α-interferon) other than anti-retroviral chemotherapy
13. Subject has participated in another clinical study involving an IP or investigational device within 30 days prior to enrollment or is scheduled to participate in another clinical study involving an IP or investigational device during the course of this study
14. Parent or legally authorized representative has a medical, psychiatric, or cognitive illness or recreational drug/alcohol use that, in the opinion of the investigator, would affect subject safety or compliance
15. Parent, legally authorized representative or subject are a member of the team conducting this study or is in a dependent relationship with one of the study team members. Dependent relationships include close relatives (ie, children, partner/spouse, siblings, parents) as well as employees of the investigator or site personnel conducting the study.

E.5 End points

E.5.1

Primary end point(s)

Incidence of FVIII inhibitor development
The success rate of ITI therapy with BAX 855

E.5.1.1

Timepoint(s) of evaluation of this end point

The set of subjects to be analyzed includes all subjects who developed a confirmed inhibitor (at any time) based on a second repeat blood sample within 2 weeks of sitenotification of an inhibitor and all subjects who did not develop an inhibitor and had ≥ 100 EDs.

E.5.2

Secondary end point(s)

Binding IgG and IgM antibodies to FVIII, PEG-FVIII and PEG
AEs and SAEs
Clinically significant changes in vital signs and clinical laboratory parameters (hematology and clinical chemistry)
Efficacy:
-Annualized bleeding rate (ABR) for prophylactic and on-demand treatment
-Number of BAX 855 infusions per bleeding episode
-Overall hemostatic efficacy rating at 24 h after initiation of treatment and at resolution of bleed
-Weight-adjusted consumption of BAX 855 per month, per year and per event (prophylaxis and treatment of bleeding episode) and the number of infusions per month and per year
Pharmacokinetics:
-IR at baseline and over time
-Half-life at baseline (optional)

E.5.2.1

Timepoint(s) of evaluation of this end point

Binding antibodies to FVIII, BAX 855 and PEG and all other secondary safety outcome measures will be analyzed descriptively.
The ABR will be analyzed by point and interval estimates derived from a negative binomial model with treatment regimen (on-demand vs. prophylaxis) as a covariate and the duration of the observation period as an offset. Other secondary efficacy outcome measures as well as IR over time will be analyzed descriptively.

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

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

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

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

Austria

Belgium

Bulgaria

Canada

Czech Republic

Denmark

France

Germany

Hong Kong

Hungary

India

Italy

Korea, Republic of

Lithuania

Malaysia

Netherlands

New Zealand

Norway

Poland

Romania

Singapore

Spain

Switzerland

Taiwan

Thailand

Turkey

Ukraine

United Kingdom

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

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:

120

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)

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

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

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

Pediatric patients under age of 6 years

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

120

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

2016-03-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-02-21

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

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