Clinical Trials Register

Summary
EudraCT Number:	2013-004343-23
Sponsor's Protocol Code Number:	IG0902
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:	2019-06-06
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

2013-004343-23

A.3

Full title of the trial

Studio per indagare le proprietà farmacocinetiche (per vedere quanto è attivo il farmaco di studio nel sangue e quanto tempo ci vuole per il farmaco di studio per uscire dal sangue), l'efficacia e la sicurezza di FIB Grifols in soggetti con carenza congenita di fibrinogeno

Studio multicentrico, prospettico, in aperto, a braccio singolo per valutare la farmacocinetica, l’efficacia e la sicurezza del fibrinogeno plasma-derivato umano (FIB Grifols) in pazienti affetti da afibrinogenemia congenita

A.3.1

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

Study investigating the pharmacokinetic properties (to see how active the study drug is in your blood and how long it takes for the study drug to get out of your blood) , efficacy and safety of FIB Grifols in subjects with congenital fibrinogen deficiency

Multicenter, Prospective, Open-Label, Single-Arm Trial to Evaluate the Pharmacokinetics, Efficacy, and Safety of Human Plasma-Derived Fibrinogen (FIB Grifols) in Patients with Congenital Afibrinogenemia

A.3.2

Name or abbreviated title of the trial where available

IG0902

A.4.1

Sponsor's protocol code number

IG0902

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02281500

A.5.4

Other Identifiers

Name:

IG0902

Number:

IG0902

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	INSTITUTO GRIFOLS, S.A.
B.1.3.4	Country	Spain
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	Instituto Grifols, S.A.
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Instituto Grifols, S.A.
B.5.2	Functional name of contact point	Bioscience Clinical and Pharmacovig
B.5.3	Address:
B.5.3.1	Street Address	Av. Generalitat 152 B.5.3.2 Town/city
B.5.3.2	Town/ city	Sant Cugat del Vallès
B.5.3.3	Post code	08174
B.5.3.4	Country	Spain
B.5.4	Telephone number	0034935712000
B.5.5	Fax number	0034935712000
B.5.6	E-mail	IGregulatory.affairs@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	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	Intravenous Fibrinogen Grifols
D.3.2	Product code	FIB Grifols
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
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	fibrinogeno umano
D.3.9.1	CAS number	9001-32-5
D.3.9.2	Current sponsor code	FIB Grifols
D.3.9.3	Other descriptive name	HUMAN FIBRINOGEN
D.3.9.4	EV Substance Code	SUB12502MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/l milligram(s)/litre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
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	Yes
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

Congenital Afibrinogenemia

afibrinogenemia congenita

E.1.1.1

Medical condition in easily understood language

Deficency of fibrinogen in human plasma

Deficienza di fibrinogeno nel plasma umano

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	10052651
E.1.2	Term	Afibrinogenaemia
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 evaluate the pharmacokinetics, efficacy, and safety of human plasmaderived fibrinogen concentrate FIB Grifols after a single-dose 70 mg/kg body weight administration.

Valutare la farmacocinetica, l’efficacia e la sicurezza del concentrato di fibrinogeno plasma-derivato umano FIB Grifols dopo la somministrazione di una dose singola di 70 mg/kg di peso corporeo.

E.2.2

Secondary objectives of the trial

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1 Male or female subjects less than 70 years old.
2 Sign the written Informed Consent Form (ICF), or the subject's parent
or legal guardian signs the ICF where applicable, and the Subject
Authorization Form (SAF) where applicable. Pediatric subjects, as
defined by local regulations, will be asked to sign an age appropriate
assent form.
3 Subjects diagnosed with congenital fibrinogen deficiency manifested
as afibrinogenemia.
4 Subjects with a fibrinogen level undetectable, or equal or less than 30
mg/dL determined by both Clauss and antigen methods at baseline.
5 Female subjects of child-bearing potential must have a negative test
for pregnancy blood or urine human chorionic gonadotropin (HCG-based
assay) at baseline
6 Female subjects of child-bearing potential and their partners have
agreed to practice contraception using a method of proven reliability
(i.e. hormonal methods, barrier methods, intrauterine devices methods,
or abstinence) to prevent a pregnancy during the course of the clinical
trial.
7 Subjects must be willing to comply with all aspects of the clinical trial
protocol, including blood sampling, for the whole duration of the study.

I soggetti (sia i soggetti adulti che pediatrici) saranno ritenuti idonei a partecipare allo studio se soddisfano TUTTI i seguenti criteri di inclusione:
1. Uomini o donne di età inferiore a 70 annia.
2. Firma del modulo di consenso informato da parte del soggetto o di un genitore o tutore dello stesso, se del caso, e firma del modulo di autorizzazione del soggetto, se pertinente. Ai soggetti pediatrici, secondo quanto definito dalle normative locali, verrà chiesto di firmare un modulo di consenso adeguato all’età.
3. Soggetti con diagnosi di deficit di fibrinogeno congenito in forma di afibrinogenemia.
4. Soggetti con livello di fibrinogeno non rilevabile1 o pari o inferiore a 30 mg/dl stabilito sia in base al metodo di Clauss, sia con il metodo di rilevamento dell’antigene al basale2 (i
campioni raccolti entro le 24 ore precedenti l’infusione effettuata durante la visita al giorno 0 saranno sottoposti ad analisi in loco) o alla visita di screening3 (i campioni devono essere raccolti almeno 14 giorni prima dell’infusione effettuata durante la visita al giorno 0 per essere sottoposti ad analisi presso il laboratorio centrale).
1Il limite di rilevamento del livello di fibrinogeno è fissato a 30 mg/dl o inferiore per entrambi i metodi.
2Per i centri che dispongono delle risorse per eseguire l’analisi dei livelli di fibrinogeno in loco sia con il metodo di Clauss che con il metodo di rilevamento dell’antigene con un limite di rilevamento di 30 mg/dl o inferiore.
3Per i centri che non dispongono delle risorse per eseguire l’analisi dei livelli di fibrinogeno in loco sia con il metodo di Clauss che con il metodo di rilevamento dell’antigene o che impiegano metodi non sufficientemente sensibili (limite di rilevamento superiore a 30 mg/dl).
5. I soggetti femmina in età fertileb devono risultare negative al test di gravidanza eseguito mediante emocromo o saggio della gonadotropina corionica umana (saggio HCG) al basale (campione raccolto entro le 24 ore precedenti l’infusione somministrata durante la visita al giorno 0).
6. I soggetti femmina in età fertileb e i rispettivi partner acconsentono ad adottare misure contraccettive impiegando metodi di comprovata efficacia (ossia, metodi ormonali, metodi meccanici, dispositivi intrauterini o astinenza) al fine di evitare una gravidanza nel corso dello studio clinico.

7. I soggetti devono accettare di aderire a tutti gli aspetti del protocollo dello studio clinico, compresa la raccolta dei campioni ematici per l’intera durata dello studio.

E.4

Principal exclusion criteria

1 Subjects who received any fibrinogen-containing product within 21
days prior to Day 0 Visit.
2 Subjects who present with active bleeding within 10 days prior to
infusion on Day 0.
3 Subjects with acquired (secondary) fibrinogen deficiency.
4 Subjects diagnosed with dysfibrinogenemia.
5 Subjects with documented history of deep vein thrombosis (DVT),
pulmonary embolism, or arterial thrombosis within
1 year prior to enrolment in this clinical trial.
6 Subjects with known antibodies against fibrinogen.
7 Subjects with a history of severe anaphylactic reactions or reactions
to any blood-derived product.
8 Subjects with a history of intolerance to any component of the
investigational product.
9 Subjects with a documented history of IgA deficiency and antibodies
against IgA.
10 Females who are pregnant or breastfeeding.
11 Subjects with renal impairment (i.e. serum creatinine exceeds more
than 2.0 times the upper limit of normal [ULN]) at baseline.
12 Subjects with aspartate aminotransferase (AST) or alanine
aminotransferase (ALT) levels exceeding more than 2.5 times the ULN at
baseline.
13 Subjects with a history of chronic alcoholism or illicit drug addiction
in the preceding 12 months prior to enrollment in this clinical trial.
14 Subjects with any medical condition which is likely to interfere with
the evaluation of the study drug and/or the satisfactory conduct of the
clinical trial according to the investigator's judgment.
15 Subjects who received aspirin-containing products and nonsteroidal
anti-inflammatory drugs (NSAIDs) within 7 days prior to the Day 0 Visit.
16 Subjects currently receiving, or having received within 3 months
prior to enrolment into this clinical trial, any investigational drug or
device.
17 Subjects who were previously administered the investigational
product FIB Grifols during this clinical trial (i.e. every subject can only
participate in the study once).
18 Subjects who are unlikely to adhere to the protocol requirements,
are likely to be uncooperative, or are unable to provide a storage serum
sample prior to investigational drug infusion.

1. Soggetti cui è stato somministrato un prodotto a contenuto di fibrinogeno nei 21 giorni precedenti la visita al giorno 0.
2. I soggetti che manifestano emorragie attive nei 10 giorni precedenti l’infusione al giorno 0.
3. I soggetti con deficit di fibrinogeno acquisito (secondario).
4. Soggetti con diagnosi di disfibrinogenemia.
5. Soggetti con precedenti documentati di trombosi venosa profonda (DVT), embolia polmonare o trombosi nell’anno precedente l’arruolamento al presente studio clinico.
6. Soggetti con presenza nota di anticorpi anti-fibrinogeno.
7. Soggetti con precedenti di reazioni anafilattiche gravi o reazioni a prodotti emoderivati.
8. Soggetti con precedenti di intolleranza a uno qualsiasi dei componenti del prodotto oggetto della sperimentazione.
9. Soggetti con precedenti documentati di deficit di IgA e anticorpi anti-IgA.
10. Soggetti femmina in stato di gravidanza o in allattamento.
11. Soggetti con insufficienza renale (ossia con livelli di creatinina nel siero oltre 2 volte il limite superiore della norma [ULN]) al basale (campione raccolto entro 24 ore prima dell’infusione della visita al giorno 0).
12. Soggetti con livelli di aspartato aminotransferasi (AST) o alanina aminotransferasi (ALT) oltre 2,5 volte l’ULN al basale (campione raccolto entro 24 ore prima dell’infusione somministrata durante la visita al giorno 0).
13. Soggetti con precedenti di alcolismo cronico o dipendenti da sostanze illecite nei 12 mesi precedenti l’arruolamento nel presente studio clinico.
14. Soggetti con qualsiasi condizione medica che possa interferire con la valutazione del farmaco in studio e/o con l’esecuzione soddisfacente dello studio clinico secondo il giudizio dello sperimentatore (ad esempio, altri disturbi emorragici congeniti o acquisiti diversi dal deficit di fibrinogeno congenito, intervento chirurgico pianificato che preveda una trasfusione di sangue).
15. Soggetti cui sono stati somministrati prodotti a contenuto di aspirina e farmaci antinfiammatori non steroidei (FANS) nei 7 giorni precedenti la visita al giorno 0.
16. Soggetti attualmente sottoposti, o che sono stati sottoposti nei 3 mesi precedenti l’arruolamento al presente studio clinico, a un qualsiasi dispositivo o farmaco sperimentale.
17. Soggetti cui è stato somministrato in precedenza il farmaco oggetto della sperimentazione FIB Grifols durante il presente studio clinico (ossia, ciascun soggetto può partecipare allo studio una sola volta).
18. Soggetti che probabilmente non rispetteranno i requisiti del protocollo, non offriranno il livello di collaborazione richiesto o non saranno in grado di produrre un campione di siero di archiviazione prima dell’infusione del farmaco oggetto della sperimentazione.

E.5 End points

E.5.1

Primary end point(s)

-AUC0-14days (Area under the curve from zero to 14 days)
-AUC0-∞ (Area under the curve from zero to infinity)
-Cmax (Maximum plasma concentration)
-tmax (Time to the observed maximum plasma concentration)
-t1/2 (Half-life)
-MRT (Mean residence time)
-Vd (Volume of distribution)
-Cl (Clearance)
-IVR (In vivo recovery)
-Change in MCF (Maximum clot firmness) measured by ROTEM (Rotational thromboelastometry)

E.5.1.1

Timepoint(s) of evaluation of this end point

At Baseline,0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion

Al Baseline,0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 e 336 ore dopo l'infusione

E.5.2

Secondary end point(s)

- Difference (improvement) in other thromboelastographic parameters:
Clotting time (CT)
Clot formation time (CFT)
Alpha angle (α)
-Difference (improvement) in standard coagulation variables from baseline to 1-hour post-infusion.
Prothrombin time (PT)
Thrombin time (TT)
Activated partial thromboplastin time (aPTT)

E.5.2.1

Timepoint(s) of evaluation of this end point

Baseline (prior to infusion), one hour after completion of infusion

Baseline (prima dell'infusione), un'ora dopo il completamento dell'infusione

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

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)

Yes

E.7.1.1

First administration to humans

Yes

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

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

Information not present in EudraCT

E.8.1.6

Cross over

Information not present in EudraCT

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.8.4.1

Number of sites anticipated in 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

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

India

Lebanon

Turkey

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

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