Clinical Trials Register

Summary
EudraCT Number:	2015-005524-26
Sponsor's Protocol Code Number:	GBI1406
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2021-05-24
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2015-005524-26

A.3

Full title of the trial

A Multicenter Phase 2 Open-Label, Single-Arm, Prospective, Interventional Study of Plasma-Derived Factor VIIII/VWF Alphanate® in Immune Tolerance Induction Therapy in Subjects with Congenital Hemophilia A.

Studio multicentrico di fase II, in aperto, a singolo braccio, prospettico, interventistico sull'uso del fattore VIII/VWF di derivazione plasmatica (Alphanate®) nella terapia di induzione dell'immunotolleranza in soggetti affetti da emofilia A congenita

A.3.1

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

This is a multicenter, multinational, prospective, single-arm, nonrandomized, open-label study of approximately 25 male subjects with congenital hemophilia A with FVIII inhibitors who will receive their first (primary)treatment with Alphanate. The study will be conducted at approximately 20 study centers.

Si tratta di uno studio multicentrico, multinazionale, prospettico, a singolo braccio, non randomizzato, in aperto, su circa 25 soggetti maschi affetti da emofilia A
congenita che ricevono il loro primo trattamento per l'induzione dell'immunotolleranza (primaria) con Alphanate. Lo studio sarà condotto in circa 20 centri.

A.3.2

Name or abbreviated title of the trial where available

A Multicenter Phase 2 Open- Label, Single-Arm, Prospective, Interventional Study of Plasma-Derived F

Studio multicentrico di fase II, in aperto, a singolo braccio, prospettico, interventistico sull'uso

A.4.1

Sponsor's protocol code number

GBI1406

A.5.4

Other Identifiers

Name:

IND/CTA Number

Number:

016703

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	GRIFOLS BIOLOGICALS INC.
B.1.3.4	Country	United States
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	Grifols Biologicals LLC
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Grifols Therapeutics LLC
B.5.2	Functional name of contact point	Donna Babiar
B.5.3	Address:
B.5.3.1	Street Address	79 T.W. Alexander Drive, 4201 Research Commons
B.5.3.2	Town/ city	Research Triangle Park, NC
B.5.3.3	Post code	27709
B.5.3.4	Country	United States
B.5.4	Telephone number	0019193162098
B.5.5	Fax number	0010000000000
B.5.6	E-mail	donna.babiar@grifols.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	ALPHANATE - 1000 U.I. POLVERE E SOLV PER SOLUZIONE PER INFUSIONE1 FLACONE DI POLVERE + 1 FLACONE DI SOLV 10ML + SIRINGA + 1 AGO A DOPPIA PUNTA + AGO-MICROFILTRO
D.2.1.1.2	Name of the Marketing Authorisation holder	Grifols Biologicals LLC
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	Alphanate
D.3.2	Product code	[GBI1406]
D.3.4	Pharmaceutical form	Powder for solution for infusion
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	FATTORE VIII UMANO DI COAGULAZIONE
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	Antihemophilic Factor/von Willebrand Factor Complex (Human)
D.3.9.4	EV Substance Code	SUB13813MIG
D.3.10	Strength
D.3.10.1	Concentration unit	IU/ml international unit(s)/millilitre
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	80 to 120
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.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

Inhibitors in patients with severe Congenital Haemophilia A

Inibitori in pazienti con grave Emofilia A Congenita

E.1.1.1

Medical condition in easily understood language

Haemophilia A is a genetic deficiency in clotting factor VIII which leads to increased bleeding. Approximately 1/3 of severe hemophilia patients develop antibodies to FVIII

L'emofilia A consiste in una deficienza genetica nella coagulazione del fattore VIII che porta ad un aumentato sanguinamento. Circa 1/3 dei pazienti emofilici gravi sviluppano anticorpi contro FVIII

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	HLT
E.1.2	Classification code	10018847
E.1.2	Term	Haematological disorders
E.1.2	System Organ Class	100000004851

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 assess the proportion of subjects who achieve complete immune tolerance within 33 months of initiating Alphanate for immune tolerance induction (ITI).
To assess the safety of Alphanate treatment for ITI

Valutare la percentuale di soggetti che raggiungono l'immunotolleranza completa entro 33 mesi dall'inizio del trattamento con Alphanate per l'induzione dell'immunotolleranza (ITI)
Valutare la sicurezza del trattamento con Alphanate per ITI

E.2.2

Secondary objectives of the trial

To assess the proportion of subjects who achieve either complete or partial immune tolerance within 33 months of initiating Alphanate for ITI.
To assess the maintenance of complete or partial immune tolerance without relapse for 12 months.
To assess the annualized frequency of bleeding events

Valutare la percentuale di soggetti che raggiungono l'immunotolleranza completa o parziale entro 33 mesi dall'inizio del trattamento con Alphanate per l'ITI
Valutare il mantenimento dell'immunotolleranza completa o parziale senza recidive per 12 mesi
Valutare la frequenza annualizzata di episodi emorragici

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

A subject must meet all of the following inclusion criteria at the time of the Screening/Baseline Visit (as specified below) to be eligible for participation in the study:
1. The subject has a documented diagnosis of severe congenital hemophilia A with FVIII:C <1% of normal.
2. The subject is a male <8 years of age at the Baseline Visit.
3. The subject's documented historical peak inhibitor titer is =10 Bethesda units (BU) and =200 BU.
4. The subject has an inhibitor titer >0.6 BU and <10 BU at Screening.
5. The subject has had a delay =24 months from the date of diagnosis of the inhibitor to the start of the subject's ITI treatment.
6. The subject has a caregiver willing to participate and comply with requirements of the protocol, including home infusions, blood
sampling, and daily diary for the duration of the trial.
7. The subject has provided signed assent, if applicable (per Institutional Review Board or Ethics Committee requirements), and a parent or legal guardian has provided signed informed consent.

I soggetti devono soddisfare tutti i seguenti criteri di inclusione al momento della visita di screening/basale (come specificato sotto) per essere idonei alla partecipazione allo studio:
1. Soggetti con diagnosi documentata di emofilia A congenita grave con FVIII:C <1% del normale.
2. Soggetti maschi di età <8 anni alla visita basale.
3. Soggetti con titolo massimo storico documentato di inibitori =10 unità Bethesda (BU) e =200 BU.
4. Soggetti con titolo di inibitori >0,6 BU e <10 BU allo screening.
5. Soggetti per i quali sono trascorsi =24 mesi dalla data della diagnosi dell'inibitore all'inizio del trattamento di ITI.
6. Soggetti assistiti da una persona disposta a partecipare e adempiere ai requisiti del protocollo, inclusi infusioni domiciliari,
prelievi di sangue e diario quotidiano per tutta la durata dello studio.
7. Soggetti che hanno fornito un assenso firmato, se applicabile (in base ai requisiti del Consiglio di revisione istituzionale o del Comitato etico) e il cui genitore o tutore legale ha fornito un consenso informato firmato.

E.4

Principal exclusion criteria

A subject meeting any of the following exclusion criteria is not eligible for participation in the study:
1. The subject has acquired factor VIII (FVIII) deficiency.
2. The subject has previously received ITI treatment.
3. The subject has a recent (within 1 month) history of central line infection at the time of Screening.
4. The subject has a high risk of cardiovascular, cerebrovascular, or thromboembolic event as judged by the investigator.
5. The subject is currently undergoing treatment with immunosuppressive drugs (eg, systemic corticosteroids), azathioprine, cyclophosphamide, high dose immunoglobulin, interferon, or the use of a protein A column or plasmapheresis and is unwilling to discontinue these treatments starting at the screening visit.
6. The subject has a known infection with human immunodeficiency virus (HIV) or has clinical signs and symptoms consistent with current HIV infection.
7. The subject has a known previous infection with hepatitis B virus or hepatitis C virus or has clinical signs and symptoms consistent with current HBV or HCV infection.
8. The subject has significant proteinuria, has a history of acute renal failure or severe renal impairment (blood urea nitrogen or creatinine >2 times the upper limit of normal), or is
receiving dialysis at Screening.
9. The subject has a value of aspartate transaminase or alanine aminotransferase >2 times the upper limit of normal at Screening.
10. The subject has clinical evidence of any significant acute or chronic disease that, in the opinion of the investigator, may interfere with successful completion of the trial or place the subject at undue medical risk.
11. The subject has a history of anaphylaxis or severe systemic reaction to any plasma-derived or other blood products.
12. The subject has participated in another clinical trial of an Investigational Product within 30 days prior to Screening—imaging studies without investigative treatments are permitted—or has received any investigational blood product within the previous 3 months.
13. In the opinion of the investigator, the subject or caregiver may have compliance problems with the protocol or the procedures of the protocol.

I soggetti che soddisfano uno qualsiasi dei seguenti criteri di esclusione non sono idonei alla partecipazione allo studio:
1.Soggetti con carenza acquisita di fattore VIII (FVIII).
2.Soggetti che hanno ricevuto precedentemente un trattamento di ITI.
3. Soggetti con precedenti recenti (entro 1 mese) di infezione della linea centrale al momento dello screening.
4. Soggetti a rischio elevato di eventi cardiovascolari, cerebrovascolari o tromboembolici secondo il parere dello sperimentatore.
5. Soggetti attualmente sottoposti a trattamento con farmaci immunosoppressori (ad es. corticosteroidi sistemici), azatioprina, ciclofosfamide, immunoglobulina ad alte dosi, interferone, colonna con proteina A o plasmaferesi e che non sono disposti a interrompere questi trattamenti a partire dalla visita di screening.
6. Il soggetto ha un'infezione nota del virus dell'immunodeficienza umana oppure mostra segni e sintomi consistenti con infezione da HIV.
7. Soggetti con infezione precedente nota da virus dell'epatite B o da virus dell'epatite C o con segni e sintomi clinici coerenti con un'infezione da HBV o HCV in corso.
8. Soggetti con proteinuria significativa, precedenti di insufficienza renale acuta o compromissione renale grave (azoto ureico nel sangue o creatinina >2 volte il limite superiore di normalità) o sottoposti a dialisi allo screening.
9. Soggetti con un valore di aspartato transaminasi o alanina aminotransferasi >2 volte il limite superiore di normalità allo screening.
10. Soggetti con evidenza clinica di qualsiasi malattia acuta o cronica significativa che, secondo lo sperimentatore, potrebbe interferire con il corretto completamento dello studio o mettere il soggetto a rischio medico inopportuno.
11. Soggetti con precedenti di anafilassi o reazione sistemica grave a un prodotto derivato dal plasma o ad altri prodotti ematici.
12. Soggetti che hanno partecipato a un altro studio clinico su un prodotto sperimentale nei 30 giorni precedenti lo screening (sono permessi studi di imaging senza trattamenti sperimentali) o che hanno ricevuto un prodotto ematico sperimentale nei precedenti 3 mesi.
13. Secondo l'opinione dello sperimentatore, soggetti o persone che li assistono che potrebbero avere problemi di adesione al protocollo o alle procedure del protocollo.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint is the proportion of subjects achieving complete immune tolerance within 33 months of initiation of ITI treatment.

L'endpoint di efficacia primaria è la percentuale di soggetti che raggiungono l'immunotolleranza completa entro 33 mesi dall'inizio del trattamento di ITI

E.5.1.1

Timepoint(s) of evaluation of this end point

within 33 months of initiation of ITI treatment

entro 33 mesi dall'inizio del trattamento di ITI

E.5.2

Secondary end point(s)

Time to achieve inhibitor titer <0.6 BU, time to complete immune tolerance, and time to partial immune tolerance. (See protocol section 5.1.3.2, paragraph 3)
The proportion of subjects who achieve either complete or partial immune tolerance within 33 months of receiving Alphanate for ITI.
The proportion of subjects who maintain complete immune tolerance or partial immune tolerance without relapse for 12 months
The annualized frequencies of bleeding events during the ITI Treatment Phase and the Prophylactic Phase

Tempo impiegato per raggiungere un titolo di inibitore <0.6 BU, tempo per raggiungere l'immunotolleranza completa, e tempo per raggiungere l'immunotolleraza parziale (far riferimento al protocolllo sez. 5.1.3.2, paragrafo 3)
La percentuale di soggetti che raggiunge o l'immonotolleranza completa o parziale entro 33 mesi dal trattamento con Alphanate per l'ITI
La percentuale di soggetti che mantiene l'immunotolleranza completa o parziale per 12 mesi senza ricadute
Le frequenze annualizzate degli eventi di sanguinamenti durante la Fase di Trattamento ITI e la Fase Profilattica

E.5.2.1

Timepoint(s) of evaluation of this end point

A. 33 months of receiving Alphanate for ITI for the proportion of subjects who achieve either complete or partial immune tolerance.
B. 12 months for The proportion of subjects who maintain complete immune tolerance or partial immune tolerance without relapse.
C. 33 months + 12 months for treatment and prophylactic phases respectively for the proportion of subjects who achieve either complete or partial immune tolerance within annualized frequencies of bleeding events during the ITI Treatment Phase and the Prophylactic Phase

A. 33 mesi di trattamento con Alphanate per l'ITI per la percentuale di soggetti che raggiunge o l'immunotolleranza completa o parziale.
B. 12 mesi per la percentuale di soggetti che mantiene l'immunotolleranza completa o parziale senza ricadute
C. 33 mesi + 12 mesi per le fasi di trattamento e profilattiche rispettivamente per la percentuale di soggetti che raggiunge o l'immunotolleranza completa o parziale entro le frequenze annualizzate di eventi di sanguinamento durante la Fase di Trattamento ITI o la Fase di profilassi

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

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

Yes

E.8.2.3.1

Comparator description

Non applicabile

Not applicable

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

Canada

India

Russian Federation

United States

Italy

Spain

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

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.1.1.1

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.1.2

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

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Target subjects are minors from age 0 to less than 8 years of age. Their enrollment in the study will be on the basis of consent from their legal representative and or legal guardian as well as impartial witness as per GCP.

I soggetti coninvolti sono minori con età variable da 0 a meno di 8 anni. Il loro arruolamento nello studio si baserà sul consenso del loro rappresentante legale o tutore così come un testimone imparziale, come richiesto da GCP.

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)

None

Nessuno

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

2016-10-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-11-17

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

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