Clinical Trials Register

Summary
EudraCT Number:	2019-000679-18
Sponsor's Protocol Code Number:	EFC15467
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-11-04
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

2019-000679-18

A.3

Full title of the trial

ATLAS-PEDS: An open-label, multinational study of fitusiran prophylaxis in male pediatric subjects aged 1 to less than 12 years with hemophilia A or B

ATLAS-PEDS: Studio in aperto, multinazionale nella profilassi con fitusiran in soggetti pediatrici di sesso maschile di età compresa fra 1 e 12 anni con emofilia A o B

A.3.1

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

Fitusiran prophylaxis in male pediatric subjects aged 1 to less than 12 years with hemophilia A or B

profilassi con fitusiran in soggetti pediatrici di sesso maschile di età compresa fra 1 e 12 anni con emofilia A o B

A.3.2

Name or abbreviated title of the trial where available

ATLAS-PEDS

A.4.1

Sponsor's protocol code number

EFC15467

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1223-4368

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/000/2019

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	GENZYME CORPORATION
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	Genzyme Corporation
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	SANOFI S.p.A.
B.5.2	Functional name of contact point	CONTACT POINT
B.5.3	Address:
B.5.3.1	Street Address	VIALE L. BODIO 37/B
B.5.3.2	Town/ city	MILANO
B.5.3.3	Post code	20158
B.5.3.4	Country	Italy
B.5.4	Telephone number	800226343
B.5.5	Fax number	0239394168
B.5.6	E-mail	informazioni.medicoscientifiche@sanofi.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	Yes
D.2.5.1	Orphan drug designation number	EU/3/14/1297; EU/3/14/1298
D.3 Description of the IMP
D.3.1	Product name	Fitusiran
D.3.2	Product code	[SAR439774]
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Fitusiran
D.3.9.1	CAS number	1609016-97-8
D.3.9.2	Current sponsor code	SAR439774
D.3.9.4	EV Substance Code	SUB190227
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	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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	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

Hemophilia A or B

Emofilia A o B.

E.1.1.1

Medical condition in easily understood language

Hemophilia A or B

Emofilia A o B.

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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10066439
E.1.2	Term	Hemophilia
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 confirm appropriate dose levels of fitusiran when administered to male pediatric participants (ages 1 to <12 years of age) with severe hemophilia A or B

Confermare i livelli di dose appropriati di fitusiran quando viene somministrato ai partecipanti pediatrici di sesso maschile (età compresa tra 1 e <12 anni) con emofilia A o B grave

E.2.2

Secondary objectives of the trial

- To characterize the safety and tolerability
- To characterize the pharmacokinetics (PK)

Caratterizzare la sicurezza e la tollerabilità
Caratterizzare la farmacocinetica (PK)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Male, aged 1 to <12 years at the time of enrollment.
- Severe hemophilia A or B (Factor VIII (FVIII) <1% or Factor IX (FIX) </=2%)
- Participants must have inhibitory antibodies to FVIII or FIX and must meet one of the following Nijmegen-modified Bethesda assay results criteria:
- Inhibitor titer of >/=0.6 BU/mL at screening, OR
- Inhibitor titer of <0.6 BU/mL at screening with medical record evidence of 2 consecutive titers >/=0.6 BU/mL, OR
- Inhibitor titer of <0.6 BU/mL at screening with medical record evidence of anamnestic response.
- Adequate peripheral venous access, as determined by the Investigator, to allow the blood draws required by the study protocol.
- Weight requirements at the time of enrollment: 8 to <45 kg
- Willing and able to comply with the study requirements and to provide signed written informed consent obtained from parent(s)/legal guardian (hereinafter the “parent”) and written or oral assent obtained from participant, per local and national requirements.

- Maschio, età compresa tra 1 e <12 anni al momento dell'arruolamento
- Emofilia grave di tipo A o B (Fattore VIII (FVIII) <1% o Fattore IX (FIX) </=2%)
- I partecipanti devono avere anticorpi inibitori a FVIII o FIX e devono soddisfare uno dei seguenti criteri, basati sui risultati del test di Nijmegen-modificato Bethesda:
- Titolo dell'inibitore >/= 0,6 BU / mL allo screening, O
- Titolo dell'inibitore <0,6 BU / ml allo screening con evidenza medica documentata di 2 titoli consecutivi >/=0,6 BU / mL, O
- Titolo dell'inibitore <0,6 BU / ml allo screening con evidenza medica documentata di una risposta anamnestica.
- Adeguato accesso venoso periferico, in base al giudizio dello Sperimentatore, per consentire i prelievi di sangue richiesti dal protocollo di studio
- Requisiti di peso al momento dell'arruolamento: da 8 a <45 kg
- Pazienti che abbiano la volontà e siano in grado di rispettare i requisiti dello studio e di fornire il consenso informato scritto firmato ottenuto dal/dai genitore/i / tutore legale (di seguito "genitore") e l'assenso scritto o orale ottenuto dal
partecipante, in accordo ai requisiti locali e nazionali.

E.4

Principal exclusion criteria

- Known co-existing bleeding disorders other than hemophilia A or B
- Antithrombin (AT) activity <60% at Screening
- Co-existing thrombophilic disorder
- Clinically significant liver disease
- Active Hepatitis C virus infection
- Acute or chronic Hepatitis B virus infection
- Acute Hepatitis A or hepatitis E infection
- HIV positive with a CD4 count of <400 cells/µL
- History of arterial or venous thromboembolism, unrelated to an indwelling venous access
- Inadequate renal function
- History of multiple drug allergies or history of allergic reaction to an oligonucleotide or N-Acetylgalactosamine (GalNAc)
- Subjects with central or peripheral indwelling catheters, with history of venous access complications leading to hospitalization and/or systemic anticoagulation therapy.
- History of intolerance to subcutaneous (SC) injection(s)
- Any other conditions or comorbidities that would make the patient unsuitable for enrollment or could interfere with participation in or completion of the study, per Investigator judgment

- Patologie emorragiche coesistenti note, diverse dall'emofilia A o B
- Attività Antitrombina (AT) <60% allo screening
- Disturbo trombofilico coesistente
- Presenza di malattia epatica clinicamente significativa
- Positività anticorpale al virus dell'epatite C
- Presenza di infezione da epatite B acuta o cronica
- Presenza di epatite acuta A o Epatite E
- Positività nota al virus dell'HIV con conta CD4 < 400 cellule/µL
- Storia pregressa di tromboembolismo arterioso o venoso, non correlato ad un accesso venoso
- Disturbi renali
- Storia di più allergie ai farmaci o storia di reazione allergica a oligonucleotide o N-Acetilgalattosamina (GalNAc)
- Soggetti con catetere centrale o periferico, con una storia di complicazioni all’accesso venoso che hanno portato a ospedalizzazione e/o terapia anticoagulante sistemica
- Storia di intolleranza alle iniezioni sottocute (SC)
- Qualsiasi condizione o comorbidità che secondo il parere dello Sperimentatore, renderebbe il paziente non idoneo all'arruolamento o che potrebbe interferire con la compliance allo studio o con il completamento del periodo di trattamento dello studio.

E.5 End points

E.5.1

Primary end point(s)

Lowering of plasma antithrombin (AT) activity level; Lowering of plasma antithrombin (AT) activity level from Day 1 pre-fitusiran dose to Day 85

Riduzione del livello dell’attività dell’antitrombina (AT) plasmatica; Riduzione del livello dell’attività dell’antitrombina (AT) plasmatica dal Giorno 1, prima della somministrazione di fitusiran, fino al Giorno 85.

E.5.1.1

Timepoint(s) of evaluation of this end point

Day 1 to Day 85

Dal giorno 1 al giorno 85

E.5.2

Secondary end point(s)

1 - Number of participants reported with adverse events; Number of participants reported with treatment-emergent adverse events (TEAEs)
2 - Pharmacokinetics (PK): Maximum plasma concentration (Cmax); Plasma samples will be collected for measurement of plasma concentrations of fitusiran such as Cmax.
3 - Pharmacokinetics (PK): Time to reach maximum plasma concentration (Tmax); To evaluate time to reach Cmax
4 - Pharmacokinetics (PK): Ctrough; To evaluate concentration observed just before investigational medicinal product (IMP) administration during repeated dosing (Ctrough)

1- Numero di pazienti che hanno riportato eventi avversi; Numero di partecipanti che hanno riportato eventi avversi emergenti durante il trattamento (TEAEs)
2- Farmacocinetica (PK): concentrazione plasmatica massima (Cmax); campioni plasmatici saranno raccolti per la misurazione della concentrazione plasmatica di fitusiran come Cmax.
3- Farmacocinetica (PK): tempo per raggiungere la concentrazione plasmatica massima (Tmax); valutare il tempo per raggiungere la Cmax
4- Farmacocinetica (PK): C through; valutare la concentrazione osservata subito prima della somministrazione a dosi ripetute del trattamento di studio (IMP) (Ctrought)

E.5.2.1

Timepoint(s) of evaluation of this end point

1 : 160 weeks
2, 3, 4 : Day 1, Day 29, Day 57

1: 160 settimane
2,.3,4: giorno 1, giorno 29, giorno 57

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

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

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)

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

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

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

Italy

Spain

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

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)

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

Legally minor patients, as defined by local regulation

Pazienti minorenni secondo la regolamentazione locale

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)

Participants completing the treatment period will be proposed to enroll in an extension study

AI soggetti che avranno completato il periodo di trattamento sarà proposto di essere arruolati nella fase di estensione dello studio

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

2019-09-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-06-04

P. End of Trial
P.	End of Trial Status	Ongoing

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