Clinical Trials Register

Summary
EudraCT Number:	2010-021162-30
Sponsor's Protocol Code Number:	Wil-24
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:	2011-12-07
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

2010-021162-30

A.3

Full title of the trial

Prospective, Open-Label, Multi-Center, Phase III Clinical Study To Investigate The Efficacy And Safety Of Human Factor VWF/VIII Concentrate (Wilate®) In Subjects With Inherited Von Willebrand Disease (VWD) Who Undergo Surgical Procedures.

Проспективно, открито, многоцентрово, фаза III клинично изпитване за изследване ефикасността и безопасността на човешки фактор VWF/VIII концентрат (Wilate®) при пациенти с унаследена болест на Von Willebrand, които подлежат на хирургични операции

A.3.1

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

This study in an open label study that is conducted in many centers around the world to investigate whether Wilate is safe and works in patients that need surgery and have von Willebrand disease.

Това проучване е открито проучване, което се провежда в много центрове по света, за да се изследва дали Wilate e безопасен и действа при пациенти, на които е необходима операция и са болни от болестта на фон Вилебранд

A.4.1

Sponsor's protocol code number

Wil-24

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	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	Octapharma AG
B.5.2	Functional name of contact point	Sigurd Knaub
B.5.3	Address:
B.5.3.1	Street Address	Seidenstrasse 2
B.5.3.2	Town/ city	Lachen
B.5.3.3	Post code	CH-8853
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	+41554512141
B.5.5	Fax number	+41554512151
B.5.6	E-mail	sigurd.knaub@octapharma.ch

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	WILATE 500 I.U.
D.3.2	Product code	WILATE 500 I.U.
D.3.4	Pharmaceutical form	Lyophilisate 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.3.9.2	Current sponsor code	Wilate
D.3.9.3	Other descriptive name	Human von Willebrand factor (VWF) and coagulation factor VIII (FVIII)
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.3.11 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)	Yes
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.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	WILATE 1000 I.U.
D.3.2	Product code	WILATE 1000 I.U.
D.3.4	Pharmaceutical form	Lyophilisate 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.3.9.2	Current sponsor code	Wilate
D.3.9.3	Other descriptive name	Human von Willebrand factor (VWF) and coagulation factor VIII (FVIII)
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)	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)	Yes
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

Surgery in Inherited Von Willebrand Disease (VWD)

Хирургична операция при унаследена болест на фон Вилебранд (VWD)

E.1.1.1

Medical condition in easily understood language

Surgery in Inherited Von Willebrand Disease

Хирургична операция при унаследена болест на фон Вилебранд

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	14.1
E.1.2	Level	PT
E.1.2	Classification code	10047715
E.1.2	Term	Von Willebrand's disease
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic disorders

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 of the study is to evaluate the overall hemostatic efficacy of Wilate® in preventing excessive intra- and post-operative bleeding in pediatric and adult subjects with VWD who require a Von Willebrand Factor (VWF) product and undergo a surgical procedure.

Основната цел на проучването е да се направи оценка на общата хемостатична ефикасност на Wilate® за предотвратяване на прекомерно интра- и следоперативно кървене при деца и възрастни пациенти с VWD, които се нуждаят от продукта с фактора на фон Вилебранд (VWF) и се подлагат на хирургична процедура.

E.2.2

Secondary objectives of the trial

• To evaluate the intra- and post-operative surgical hemostatic efficacy of Wilate® in preventing excessive bleeding in pediatric and adult subjects with VWD who require a VWF product and undergo a surgical procedure.
• To assess the safety of Wilate® used in VWD subjects who undergo surgical procedures.

• To document the capability of Wilate® to normalize the coagulation defect in VWD as demonstrated by an increase of the plasma activity of von Willebrand Factor Ristocetin cofactor (VWF:RCo) and Factor VIII:Coagulant (FVIII:C).

• To analyze the actual dosage and duration of treatment in surgical procedures.

• Да се направи оценка на интра- и следоперативната хирургическа хемостатична ефикасност на Wilate® за предотвратяване на прекомерно кървене при деца и възрастни пациенти с VWD, които се нуждаят от продукта VWF и се подлагат на хирургична процедура.
• Да се направи оценка на безопасността на Wilate®, използван при пациенти с VWD, които се подлагат на хирургични процедури.
• Да се документира способността на Wilate® за нормализиране на коагулационния дефект при VWD, демонстрирано от увеличението на плазмената активност на Фактора на фон Вилебранд Ристоцетин кофактор (VWF:RCo) и Фактор VIII: Коагулант (FVIII:C).
• Да се анализира действителната доза и продължителността на лечение при хирургични процедури.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male and female subjects who are at least 6 years of age.
2.Diagnosed with congenital VWD (any type) where VWF:RCo is below 40% at screening or the subject has a diagnosis of Type 1, 2 or 3 VWD and a history of VWF:RCo below 40% documented in their medical notes at enrolment.
3.Require therapy with a VWF product to treat any potential surgical procedure.
4. Negative for anti-human immunodeficiency virus (HIV); if positive, viral load <200 particles/μL or <400,000 copies/mL and CD4+ count > 200/μL.
5. The subject and/or their legally acceptable representative understands the nature of the study, gives written informed consent to participate in the study and is willing and able to comply with the protocol.

• Мъже и жени, които са на възраст най-малко 6 години.
• Диагностицирани с вроден VWD (всеки тип) , при които VWF:RCo е под 40% според резултатите от скрининг теста или пациенти с диагноза VWD тип 1, 2 или 3 и данни за нива на VWF:RCo ипод 40%, документирани в медицинските им досиета при записването за участие в проучването.
• Необходимост от терапия с продукт VWF за лечение във връзка с потенциални хирургични процедури.
• Отрицателен резултат на тест за антитела срещу човешки имунодефицитен вирус (HIV); при положителен резултат, вирусен товар <200 частици/µL или <400 000 копия/µL и CD4+ брой > 200/μL.
• Пациентите и/или техните законни представители разбират естеството на проучването, дават писменото си информирано съгласие за участие в проучването и желаят и могат да спазят изискванията на протокола.

E.4

Principal exclusion criteria

1. Known coagulation disorder other than congenital VWD.
2. Any VWF containing product administered within 3 days prior to the screening visit.
3. Any subject where it is planned to infuse the investigational product via continuous infusion.
4. Have a known history of, or are suspected to have VWF or FVIII inhibitors.
5. Emergency surgery or any surgery with a degree of urgency not permitting completion of baseline assessment required by the study protocol.
6. Suffering an acute or chronic medical condition, other than VWD, which may in the opinion of the Investigator affect the conduct of the study.
7. Subjects with active hepatic disease (alanine aminotransferase [ALT] or aspartate aminotransferase [AST] levels >5 times the upper limit of normal)8. Have a known or suspected hypersensitivity or previous evidence of severe side effects to Wilate® or other VWF/FVIII concentrates.
9. Subjects receiving immune-modulating drugs (other than anti-retroviral chemotherapy) such as alpha-interferon, prednisone (equivalent to >10 mg/day), or similar drugs at study start.
10. Pregnant women within the first 20 weeks of gestation.
11. Subjects having evidence or a history (within the previous 12 months) of abuse of any drug substance, licit or illicit.
12. Participation in another interventional clinical study currently or during the past 4 weeks.

• Има данни за коагулационно разстройство, различно от вродена VWD.
• Прилагане на VWF съдържащи продукти в рамките на 3 дни преди скрининг посещението.
• Пациенти, при които е планирано да се влива изпитвания продукт чрез продължително вливане.
• Данни за анамнеза или съмнения за наличие на VWF или FVIII инхибитори.
• Спешни операции или операции със степен на неотложност, не позволяваща извършване на оценка на изходното ниво, изисквана от протокола на проучването.
• Страдащи от остро или хронично заболяване, различно от VWD, което по мнение на изследователя може да повлияе на резултатите от проучването.
• Пациенти с активно чернодробно заболяване ( аланин аминотрансфераза [ALT] или аспартат аминотрансфераза[AST] нива > 5 пъти над горната граница на нормата)
• Данни или подозрения за свръхчувствителност или предишна доказателства за тежки странични реакции към Wilate® или други VWF/FVIII концентрати.
• Пациенти, приемащи имунно-модулиращи лекарства (различни от антиретровирусна химиотерапия), като например алфа-интерферон, преднизон (еквивалентно на > 10 мг/ден) или подобни лекарства в началото на проучването.
• Бременни жени в първите 20 седмици на бременността.
• Пациенти с данни или анамнеза (в рамките на предходните 12 месеца) за злоупотреба с лекарствени вещества, законни или незаконни.
• Участие в други интервенционални клинични проучвания в този момент или в рамките на последните 4 седмици.

E.5 End points

E.5.1

Primary end point(s)

Overall hemostatic efficacy (success or failure) of Wilate® in the treatment of VWD subjects who undergo a surgical procedure, based on both the intra-operative assessment of the surgeon and the assessment by the Investigator covering the post-surgical period from the end of the procedure to 24 hours following the last infusion, both of which use a 4-point ordinal hemostatic efficacy scale. The overall efficacy is assessed according to a pre-defined algorithm.

Общата хемостатична ефикасност (успех или неуспех) на Wilate® при лечението на пациенти с VWD, които са подложени на хирургична процедура, въз основа на интраоперативната оценка на хирурга и оценката на изследователя, наблюдаващ следоперативния период от края на процедурата до 24 часа след последното вливане, при което и двамата използват 4-степенна скала за оценка на ефикасността на хемостазата. Общата ефикасност се оценява в съответствие с предварително определен алгоритъм.

E.5.1.1

Timepoint(s) of evaluation of this end point

Overall hemostatic efficacy of Wilate® in the treatment in VWD subjects who undergo a surgical procedure based on both the intra-operative assessment of the surgeon at the end of the surgical procedure (last suture) and the assessment by the Investigator covering the post-surgical period from the end of the procedure to 24 hours following the last infusion.

Общата хемостатична ефикасност на Wilate® при лечението на пациенти с VWD, които са подложени на хирургична процедура, въз основа на интраоперативната оценка на хирурга в края на хирургичната процедура (последен шев) и оценката на изследователя, наблюдаващ следоперативния период от края на процедурата до 24 часа след последното вливане

E.5.2

Secondary end point(s)

• Assessment of intra-operative hemostatic efficacy according to 4-point ordinal efficacy scales.
• Assessment of post-operative hemostatic efficacy according to 4-point ordinal efficacy scales.
• Documentation of the actual dosage and duration of treatment during surgical procedures.
• Measurement of VWF:RCo and FVIII:C plasma activity during treatment.
• The nature and incidence of adverse events (AEs).
• Assessment of the in vivo recovery (IVR) of VWF:RCo, VWF:Ag, and FVIII:C.

• Оценка на интраоперативната хемостатична ефикасност според 4-степенна скала за оценка на ефикасността.
• Оценка на следоперативната хемостатична ефикасност според 4-степенна скала за оценка на ефикасността.
• Документиране на действителната доза и продължителността на лечението по време на хирургични процедури.
• Измерване на плазмената активност на VWF:RCo и FVIII:C по време на лечението.
• Естеството и честотата на нежелани събития (НС).
• Оценка на ин виво възстановяване (ИВВ) на VWF:RCo, VWF:Ag и FVIII:C.

E.5.2.1

Timepoint(s) of evaluation of this end point

• The intra-operative efficacy of Wilate® during the surgical procedures will be assessed by a 4-point ordinal efficacy scale by the surgeon at the end of the surgical procedure (last suture).
• Documentation of the actual dosage and duration of treatment during surgical procedures will be assessed at the end of the surgical procedure (last suture).
• Measurement of VWF:RCo and FVIII:C plasma activity during treatment will be assessed during full course of treatment
• The nature and incidence of adverse events (AE) will be assessed at the end of the study
• Assessment of the in vivo recovery (IVR) of VWF:RCo, VWF:Ag, and FVIII will be calculated at baseline from samples obtained pre infusion, 0.5, and 1 hour post-infusion.

• Интраоперативната ефикасност на Wilate® по време на хирургичните процедури ще бъде оценена по 4-степенна скала за оценка на ефикасността от хирурга в края на хирургичната процедура (последен шев)
• Документацията за актуалната приложена дозировка и продължителност на лечението по време на хирургичната процедура ще бъдат оценени в края на хирургичната процедура (последен шев)
• Измерването на плазмената активност на VWF:RCo и FVIII:C по време на лечението ще бъде оценявано по време на цялото лечение
• В края на проучването ще бъдат оценени естеството и честотата на нежелани събития (НС)
• Оценка на ин виво възстановяване (ИВВ) на VWF:RCo, VWF:Ag и FVIII ще бъде направена на изходното ниво от проби, взети преди вливането, 0,5 и 1 час след вливането

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

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

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

India

Russian Federation

Turkey

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

ПВПП

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:

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)

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 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 2011-12-07.

Yes

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

Yes

F.3.3.4

Nursing women

Yes

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

The subject and/or their legally acceptable representative understands the nature of the study, gives written informed consent to participate in the study and is willing and able to comply with the protocol.

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)

Standard care treatment is planned after the patient has ended the participation in the trial.

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

2011-12-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-12-20

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

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