Clinical Trials Register

Summary
EudraCT Number:	2017-005197-19
Sponsor's Protocol Code Number:	SIPPET2
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2019-03-14
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2017-005197-19

A.3

Full title of the trial

Inhibitor development in previously untreated patients with severe haemophilia A, first treated with plasma-derived factor VIII and then switched to recombinant product: an international, multicentre, prospective, controlled, randomized, open label, clinical trial

Sviluppo di inibitore in pazienti con emofilia A grave non precedentemente trattati, e successivamente trattati, prima, con prodotti di fattore VIII purificato da plasma e poi con prodotti di fattore VIII ricombinante: uno studio clinico internazionale, multicentrico, prospettico, controllato, randomizzato, open-label

A.3.1

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

Study to evaluate if switching from plasma-derived factor VIII products to recombinant factor VIII products lead to an increased inhibitor development in patients with hemophilia A

Studio per valutare se il passaggio da prodotti plasma derivati di fattore VIII a prodotti ricombinanti di fattore VIII non provochi un aumento di inibitore contro il fattore VIII in pazienti con emofilia A

A.3.2

Name or abbreviated title of the trial where available

Risk of inhibitor development after 50 exposure days to factor VIII

Rischio di sviluppo di inibitore dopo 50 giorni di esposizione al fattore VIII

A.4.1

Sponsor's protocol code number

SIPPET2

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	FONDAZIONE IRCCS CA' GRANDA OSPEDALE MAGGIORE POLICLINICO
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Non-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	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
B.5.2	Functional name of contact point	UOC Medicina Generale - Emostasi e
B.5.3	Address:
B.5.3.1	Street Address	Via Pace, 9
B.5.3.2	Town/ city	Milano
B.5.3.3	Post code	20122
B.5.3.4	Country	Italy
B.5.4	Telephone number	0255035414
B.5.5	Fax number	0254100125
B.5.6	E-mail	flora.peyvandi@policlinico.mi.it

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	KLOTT - 500 UI/10 ML POLV E SOLVENTE PER SOLUZIONE PER INFUSIONE 1 FLAC.NO POLVERE + 1 FLAC.NO SOLVENTE DA 10 ML + SET PER LA RICOSTITUZIONE/SOMMINISTRAZION
D.2.1.1.2	Name of the Marketing Authorisation holder	KEDRION S.P.A.
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	Fattore VIII plasma-derivato
D.3.2	Product code	pdFVIII
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	FATTORE VIII DI COAGULAZIONE DEL SANGUE UMANO DA FRAZIONAMENTO DEL PLASMA
D.3.9.2	Current sponsor code	pdFVIII
D.3.9.3	Other descriptive name	FATTORE VIII DI COAGULAZIONE DEL SANGUE UMANO DA FRAZIONAMENTO DEL PLASMA
D.3.10	Strength
D.3.10.1	Concentration unit	IU/kg international unit(s)/kilogram
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	40
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
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	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	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	Yes
D.2.1.1.1	Trade name	ADVATE - 500 UI POLVERE E SOLVENTE PER SOLUZIONE INIETTABILE 1 FLACONCINO + 1 FLACONCINO 5 ML USO ENDOVENOSO
D.2.1.1.2	Name of the Marketing Authorisation holder	BAXTER AG
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	Fattore VIII ricombinante
D.3.2	Product code	rFVIII
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	FATTORE VIII DELLA COAGULAZIONE RICOMBINANTE
D.3.9.2	Current sponsor code	rFVIII
D.3.9.3	Other descriptive name	FATTORE VIII DELLA COAGULAZIONE RICOMBINANTE
D.3.10	Strength
D.3.10.1	Concentration unit	IU/kg international unit(s)/kilogram
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	40
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
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	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

Severe hemophilia A

Emofilia A grave

E.1.1.1

Medical condition in easily understood language

Severe hemophilia A

Emofilia A grave

E.1.1.2

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
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

Aim of the study is to assess whether or not switching to the use of a rFVIII (standard and extended half-life) product after the period of higher risk for inhibitor occurrence (first 50 EDs) is as safe as continuing with plasma-derived products lifelong, with no occurrence of a new peak of inhibitor development

Lo scopo del presente studio clinico è quello di valutare se i pazienti affetti da emofilia A grave trattati con prodotti plasma derivati di fattore VIII durante i primi 50 giorni di esposizione e poi passati all’utilizzo con prodotti ricombinanti di fattore FVIII abbiano un rischio simile di sviluppo dell'inibitore rispetto a quelli trattati continuamente con i prodotti plasma-derivati.

E.2.2

Secondary objectives of the trial

to investigate the frequency of transient inhibitors; the modality of occurrence of inhibitors (number of EDs, titre at onset etc.); the clinical factors potentially associated to inhibitor development (age at first treatment, family history of haemophilia, family history of inhibitor, surgery, severity of treatment); the laboratory measurable factors potentially involved in inhibitor development (FVIII gene defect, FVIII antigen levels, subclass of inhibitor, epitope mapping); the incidence of any potential adverse event related to this proposed treatment schedule.
As ancillary end-points, the bleeding history will be evaluated measuring the annualized bleeding rate (ABR).

• Valutazione della frequenza degli inibitori transienti • Valutazione della modalità di sviluppo degli inibitori (numero di EDs, titolazione al momento della comparsa, etc) • Valutazione di fattori clinici potenzialmente associati allo sviluppo dell’inibitore (età di somministrazione del primo trattamento, storia famigliare di emofilia, storia famigliare di inibitore, chirurgia, intensità del trattamento). • Valutazione dei fattori di laboratorio potenzialmente associati allo sviluppo dell’inibitore (difetto genico del fattore VIII, livelli antigenici di fattore VIII, sottoclassi di inibitore, mappatura di epitopi) • Valutazione dell’incidenza di tutti gli altri eventi avversi correlati e non ai prodotti in studio.
Obiettivi ancillari: • Valutazione della storia medica relativa agli episodi di
sanguinamento (rate di sanguinamento annuale, ABR)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male subjects
2. Any ethnicity
3. Age < 6 years
4. Severe haemophilia A (FVIII:C < 1% as confirmed at enrolment by the central laboratory (those patients diagnosed locally as severe but subsequently found to have measurable FVIII ( ≥ 1%) will be considered screening failure).
5. Previously untreated patients (0 ED to any FVIII concentrates or blood products) or minimally treated (< 5 EDs) with blood components (whole blood, packed red blood cells, platelets, cryoprecipitate or fresh frozen plasma)
6. Negative inhibitor measurement at both local and central laboratory at screening, i.e., before any treatment with a FVIII concentrate
7. Ability to comply with study requirements
8. Signed informed consent of legal tutors

• Soggetti di sesso maschile
• Qualsiasi etnia
• Eta' <6 anni
• Emofilia A grave (FVIII:C <1%), come confermato dal laboratorio
• Soggetti precedentemente non trattati (0 giorni di esposizione verso qualsiasi concentrato FVIII o prodotti plasmatici) o minimamente trattati (<5 giorni di esposizione) con componenti del sangue, ossia sangue intero, plasma fresco congelato, sacche di globuli rossi, piastrine o crioprecipitati
• Inibitore negativo allo screening sia presso il laboratorio locale che presso quello centrale
• Capacità di rispettare i requisiti dello studio
• Firma del Consenso Informato dei legali rappresentanti

E.4

Principal exclusion criteria

1. Previous history of inhibitor
2. Other congenital or acquired bleeding defects
3. Plasma FVIII level ≥ 1% as assayed at the central laboratory. Patients diagnosed locally as severe and not confirmed by the central evaluation will be considered screening failure and excluded from the study.
4. Concomitant congenital or acquired immunodeficiencies
5. Concomitant treatment with systemic immunosuppressive drugs

• Precedente storia medica di sviluppo di inibitore contro il fattore VIII
• Altri difetti di sanguinamento congeniti o acquisiti diversi da Emofilia A
• Livelli plasmatici FVIII ≥1% valutati dal laboratorio centrale
• Immunodeficienza concomitante, congenita o acquisita
• Terapie concomitanti sistemiche con farmaci immunosoppressivi

E.5 End points

E.5.1

Primary end point(s)

The primary end-point is the development of inhibitors during 50-100 EDs, centrally confirmed, and non-transient.

sviluppo di inibitore, non transitorio, contro il fattore VIII durante 50-100 giorni di esposizione a prodotti di trattamento di fattore VIII

E.5.1.1

Timepoint(s) of evaluation of this end point

Inhibitor monitoring will include an assessment at the central laboratory with a Nijmegen-modified Bethesda assay 1) at screening, 2) every 5 EDs, for the first 20 EDs, then 3) every 10 EDs for the remaining 30 EDs or at any time inhibitor development will be clinically suspected, 4) after the first 50 EDs, again 5) every 5 EDs, for the additional first 20 EDs, 6) every 10 EDs for the last 30 EDs and 7) at the end of the study or at any time inhibitor development will be clinically suspected. Patients will be followed until inhibitor development or until 100EDs, whichever comes first.

La valutazione dell'inibitore verrà effettuata allo screening, ogni 5 giorni di esposizione per i primi 20 giorni di esposizione, quindi ogni 10 giorni di esposizione tra il 21esimo e il 50esimo giorno di esposizione o in qualunque momento lo sviluppo dell'inibitore sarà clinicamente ritenuto sospetto. Dopo i primi 50 giorni di esposizione, di nuovo ogni 5 giorni di esposizione tra il 51esimo e il 70esimo giorno di esposizione, e ogni 10 giorni di esposizione fino alla fine dello studio o in qualsiasi momento lo sviluppo inibitore sarà clinicamente sospettato in entrambi i bracci. I pazienti saranno seguiti fino allo sviluppo di inibitore o fino a un totale di 100 giorni di esposizione.

E.5.2

Secondary end point(s)

E.5.2.1

Timepoint(s) of evaluation of this end point

At the end of the study

Al termine dello studio

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)

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

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)

Yes

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

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

Egypt

India

Iran, Islamic Republic of

Saudi Arabia

South Africa

United States

E.8.7

Trial has a data monitoring committee

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

Premature achievement of the primary endpoint

Raggiungimento prematuro dell'endpoint primario

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)

Yes

F.1.1.3.1

Number of subjects for this age range:

100

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

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

Patients in pediatric age

Pazienti in età pediatrica

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

200

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)

the patients will continue to be treated also at the end of the study according to the standard of care of the local centre

poiché lo studio non interferisce con gli interventi clinici standard, i pazienti continueranno ad essere seguiti presso i centri ospedalieri di riferimento secondo gli standard clinici vigenti

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

2018-08-01

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-03-27

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2021-08-31

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