Clinical Trials Register

Summary
EudraCT Number:	2005-005697-71
Sponsor's Protocol Code Number:	060402
National Competent Authority:	Poland - Office for Medicinal Products
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-05-07
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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Poland - Office for Medicinal Products

A.2

EudraCT number

2005-005697-71

A.3

Full title of the trial

Antihemophilic Factor (Recombinant) Plasma/Albumin-Free Method (rAHF PFM): A Phase 3/4, Prospective, Controlled, Randomized, Multi-Center Study to Compare the Efficacy and Safety of Continuous Infusion (CI) versus Intermittent Bolus Infusion (BI) in Subjects with Severe or Moderately Severe Hemophilia A Undergoing Major Orthopedic Surgery

A.3.1

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

The main goal of the study is to compare the safety and effectiveness of administering ADVATE using either continuous infusion or single, large dose infusions during and post surgery for patients requiring major orthopedic surgery

A.3.2

Name or abbreviated title of the trial where available

Advate Randomized Surgery

A.4.1

Sponsor's protocol code number

060402

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT00357656

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	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 Innovations GmbH
B.5.2	Functional name of contact point	Judit Koranyi, MD - ClinOps
B.5.3	Address:
B.5.3.1	Street Address	Industriestraße 67
B.5.3.2	Town/ city	Vienna
B.5.3.3	Post code	1221
B.5.3.4	Country	Austria
B.5.4	Telephone number	+431201003301
B.5.5	Fax number	+43120100534
B.5.6	E-mail	judit_koranyi@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	Yes
D.2.1.1.1	Trade name	Advate (rAHF - PFM)
D.2.1.1.2	Name of the Marketing Authorisation holder	Baxter AG
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	ADVATE (rAHF-PFM)
D.3.2	Product code	not applicable
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	OCTOCOG ALFA
D.3.9.1	CAS number	139076-62-3
D.3.9.3	Other descriptive name	human coagulation factor VIII (rDNA)
D.3.9.4	EV Substance Code	SUB16449MIG
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	500 to 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)	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	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

Subjects with Severe or Moderately Severe Hemophilia A (baseline
factor VIII (FVIII) level <= 2% of normal) hemophilia A undergoing major orthopedic surgery

E.1.1.1

Medical condition in easily understood language

Subjects with Severe or Moderately Severe Hemophilia A (baseline
factor VIII (FVIII) level <= 2% of normal) hemophilia A undergoing major orthopedic surgery

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	18.0
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

The primary objective is to compare the hemostatic efficacy of CI versus intermittent BI in the peri- and post-operative setting employing rAHF-PFM in PTPs with severe or moderately severe hemophilia A (baseline FVIII level ≤ 2% of normal) undergoing
elective unilateral major orthopedic surgery that requires drain
placement by assessing the cumulative packed red blood cell (PRBC)
volume in the drainage fluid during the first 24 hours following surgery.

E.2.2

Secondary objectives of the trial

• Efficacy
1. To assess and compare the total amount of hemoglobin in the
drainage fluid
2. To determine the blood loss compared with the predicted blood loss
3. To determine the blood loss compared with the predicted blood loss until removal of drain
4. To determine the number of bleeding episodes during treatment with CI or BI
5. To record the occurrence and dimensions of any clinically relevant
postoperative hematomas
6. To assess the number of units of PRBCs transfused
7. To assess and compare the global hemostatic efficacy of rAHF-PFM
using an exploratory score between subjects receiving CI versus BI.
8. To determine the total weight-adjusted dose of rAHF-PFM per subject
9. To calculate the total daily intra- and post-operative weight-adjusted dose of rAHF-PFM during administration of CI or BI
• Safety
1. To record the number of adverse experiences (AEs) related to the
administration of the study product
2. To identify the incidence of FVIII antibody formation

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.The subject or the subject’s legally authorized representative has provided signed informed consent.
2.The subject is within 18 to 70 years of age.
3.The subject has severe or moderately severe hemophilia A, defined by a baseline FVIII level ≤ 2% of normal, as tested at screening. A subset of 15 subjects per group must have baseline FVIII levels < 1% of normal.
4.The aPTT must be within the range of normal after administration of FVIII concentrate, as determined in the preoperative pharmacokinetic evaluation, or as documented in the medical history, if available.
5.The subject is scheduled to undergo an elective unilateral major orthopedic surgery that requires drain replacement.
6.The subject was previously treated with FVIII concentrate(s) for a minimum of at least 150 exposure days prior to study entry.
7.Human immunodeficiency virus (HIV) positive subjects must be immunocompetent as determined with a CD4 count ≥ 200 cells/mm³ (CD4 count at screening), but HIV negative subjects with a CD count < 200 cells/mm³ qualify, if immunocompetency is documented.
8.The subject has a life expectancy of at least 28 days from the day of surgery.

E.4

Principal exclusion criteria

1. The subject has a detectable FVIII inhibitor at screening, with a titer ≥ 0.4BU (Nijmegen modification of the Bethesda Assay) in the central laboratory.
2.The subject has a history of FVIII inhibitors with a titer ≥ 0.4BU (by
Nijmegen assay) or ≥ 0.5 BU (by Bethesda assay) at any time prior to
screening.
3.The subject is scheduled to undergo any other concurrent minor or
major surgery during the course of the study. The placement of central venous lines and the performance of fine needle aspiration biopsies are permitted.
4. Excluding hemophilia-related physical impairments, the subject is
assigned to NYHA class ≥ III according to the New York Heart Association (NYHA).
5.The subject has an abnormal renal function (serum creatinine > 1.5
mg/dL).
6.The subject has active hepatic disease (alanine aminotransferase
[ALT] or aspartate aminotransferase [AST] levels > 5 times the upper
limit of normal).
7.The subject has severe chronic liver disease as evidenced by, but not limited to, any of the following: International Normalized Ratio (INR) >1.4, hypoalbuminemia, portal vein hypertension including presence of otherwise unexplained splenomegaly and history of esophageal varices.
8.The subject has clinical and/or laboratory evidence of abnormal
hemostasis from causes other than hemophilia A (e.g., late-stage chronic liver disease, immune thrombocytopenic purpura).
9.The subject is currently receiving, or is scheduled to receive during the course of the study, an immunomodulating drug other than antiretroviral chemotherapy (e.g., α-interferon, corticosteroid agents at a dose equivalent to hydrocortisone greater than 10 mg/day).
10.The subject has a known hypersensitivity to mouse or hamster
proteins.
11.The subject has received another investigational drug within 30 days prior to screening and/or is scheduled to receive additional
investigational drug during the course of the trial in the context of
another investigational drug study.
12.The subject is identified by the investigator as being unable or
unwilling to cooperate with study procedures.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint will be a comparison of the cumulative PRBC volume in the drainage fluid during the first 24 hours following surgery in subjects receiving rAHF-PFM by BI or CI.

E.5.1.1

Timepoint(s) of evaluation of this end point

postoperative day 1

E.5.2

Secondary end point(s)

1. Efficacy
1. Actual postoperative blood loss during the first 24 hours compared
with the average blood loss as predicted preoperatively by the operating surgeon
2. Actual postoperative blood loss compared to the expected average
blood loss until drain removal as predicted preoperatively by the surgeon
3. Number of bleeding episodes during treatment with CI or BI through postoperative Day 7
4. Number of units of PRBCs transfused

2. Safety
1. Number of AEs related to the administration of the study product
2. Incidence of FVIII inhibitory antibody (≥0.4 BU using the Nijmegen
modification of the Bethesda assay) formation.

3. Exploratory Outcome Measures
1. Total amount of hemoglobin in the cumulative drainage fluid during the first postoperative 24 hours and until time of drain removal, if drainage continues beyond 24 hours
2. Occurrence and dimensions of any clinically relevant postoperative
hematomas
3. Determination of an exploratory global hemostatic efficacy
assessment score (GHEA), which is composed of 3 different categories:
a. Assessment of intra-operative hemostatic efficacy of rAHF-PFM
performed by the operating surgeon, and
b. Assessment of blood loss in drains within the first 24 hours
postoperatively performed by the operating surgeon, and
c. Assessment of postoperative hemostatic efficacy of rAHF-PFM at
postoperative Day 8 performed by the investigator.
4. Total weight-adjusted dose of rAHF-PFM per subject through
postoperative Day 7 (IU/kg body weight/subject)
5. Total daily intra- and postoperative weight-adjusted dose of rAHF-PFM (IU/kg body weight/subject)
6. Pharmacokinetic parameters: AUC 0-48h, total AUC, AUMC, T 1/2, CL, MRT, Vss, Cmax and IR

E.5.2.1

Timepoint(s) of evaluation of this end point

English 1. Efficacy
1.First postoperative 24 hours.
2.until time of drain removal, if drainage continues beyond 24 hours
3.Post-operative day 8
4.Post-operative day 8

2. Safety
1.End-of-study visit.
2.End-of-study visit.

3. Exploratory Outcome Measures
1.First postoperative 24 hours and until time of drain removal, if
drainage continues beyond 24 hours
2.Post-operative day 8
3.Post-operative day 8
4.Post-operative day 7
5. end of study period
6. PK assessment

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

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)

Yes

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

Yes

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

rAHF-PFM

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

Austria

Belgium

France

Hungary

Italy

Netherlands

Norway

Poland

Portugal

Spain

Sweden

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

last visit of 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

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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2013-05-07.

Yes

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

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)

Patients will return to standard care as per the practice of the institution where they are treated

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

2013-08-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-05-13

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-12-09

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials