Clinical Trials Register

Summary
EudraCT Number:	2016-004087-19
Sponsor's Protocol Code Number:	EFC15110
National Competent Authority:	Ireland - HPRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2017-09-08
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

Ireland - HPRA

A.2

EudraCT number

2016-004087-19

A.3

Full title of the trial

ATLAS-PPX: an open-label, multinational, switching study to describe the efficacy and safety of fitusiran prophylaxis in patients with hemophilia A and B previously receiving factor or bypassing agent prophylaxis.

A.3.1

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

A study of fitusiran in hemophilia A and B patients previously receiving factor or bypassing agent prophylaxis

A.3.2

Name or abbreviated title of the trial where available

ATLAS-PPX

A.4.1

Sponsor's protocol code number

EFC15110

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	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	PPD Global
B.5.2	Functional name of contact point	Project Management
B.5.3	Address:
B.5.3.1	Street Address	929 North Front Street
B.5.3.2	Town/ city	Wilmington
B.5.3.3	Post code	28401
B.5.3.4	Country	United States
B.5.6	E-mail	Bettina.Schwell@ppdi.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	SUB130859
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
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	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)	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.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.2.1.2	Country which granted the Marketing Authorisation	Ireland
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	1609016978
D.3.9.2	Current sponsor code	SAR439774
D.3.9.4	EV Substance Code	SUB130859
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
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	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)	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 Hemophilia B

E.1.1.1

Medical condition in easily understood language

Hemophilia is an inherited bleeding disorder in which the blood does not clot normally and can result in internal bleeding into the muscles and joints.

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	10060613
E.1.2	Term	Hemophilia A (Factor VIII)
E.1.2	System Organ Class	100000004850

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	10060614
E.1.2	Term	Hemophilia B (Factor IX)
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 characterize the frequency of bleeding episodes while receiving fitusiran treatment, relative to the frequency of bleeding episodes while receiving factor or bypassing agent (BPA) prophylaxis

E.2.2

Secondary objectives of the trial

To characterize the following while receiving fitusiran treatment, relative to receiving factor or BPA prophylaxis:the frequency of spontaneous bleeding episodes, the frequency of joint bleeding episodes and health related quality of life (HRQOL) in patients ≥17 years of age

To characterize the frequency of bleeding episodes during the onset period in patients receiving fitusiran

To characterize the safety and tolerability of fitusiran

To characterize the annualized weight-adjusted consumption of factor/BPA while receiving fitusiran treatment, relative to receiving factor or BPA prophylaxis

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Males ≥12 years of age.

Severe hemophilia A or B as evidenced by:
a.A central laboratory measurement or documented medical record evidence of FVIII <1% or FIX level ≤2% at Screening.

A minimum of 2 bleeding episodes requiring BPA treatment within the last 6 months prior to Screening. for patients with inhibitory antibodies to factor VIII or factor IX (Cohort A). A minimum of 1 bleeding episode requiring factor treatment within the last 12 months prior to Screening for patients without inhibitory antibodies to factor VIII or factor IX (Cohort B).

Must meet either the definition of inhibitor or non-inhibitor patient as below:

Inhibitor:
Use of BPAs for prophylaxis and for any bleeding episodes for at least the last 6 months prior to Screening, and 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

The subgroup of patients in Cohort A patients must additionally meet the following criteria to be eligible to start treatment with fitusiran directly after the screening period:
- Hemophilia B with inhibitory antibody to Factor IX as defined above
- Not reposnding adequately to BPA treatment (historical ABR ≥ 20) prior to enrollment.
- In the opinion of the Investigator, with approval of Sponsor Medical Monitor, 6 month BPA prophylaxis period should be omitted.

Non-inhibitor:
Use of factor concentrates for prophylaxis and for any bleeding episodes for at least the last 6 months prior to Screening, and meet each of the following criterion:
Nijmegen-modified Bethesda assay inhibitor titer of <0.6 BU/mL at Screening and
No use of bypassing agents to treat bleeding episodes for at least the last 6 months prior to Screening and
No history of immune tolerance induction therapy within the past 3 years prior to Screening.

Prescribed prophylactic treatment (documented in the medical or pharmacy records) of hemophilia with factor concentrates or BPAs for at least 6 months prior to Screening; the regimen must be consistent with the approved prescribing information for the product or local recommendations, allowing for adjustment to individual patient response, and designed to decrease spontaneous bleeding.

Adherent to the prescribed prophylactic therapy for at least 6 months prior to Screening per Investigator assessment.

Willing and able to comply with the study requirements and to provide written informed consent and assent in the case of patients under the age of legal consent, per local and national requirements.

E.4

Principal exclusion criteria

Patients with known co-existing bleeding disorders other than hemophilia A or B

Patients with clinically significant liver disease

Patients known to be HIV positive and have a CD4 count <200 cells/μL

Patients with a history of arterial or venous thromboembolism

Estimated glomerular filtration rate ≤45 mL/min/1.73m2 (using the Modification of Diet in Renal Disease [MDRD] formula)

Patients with a co-existing thrombophilic disorder

Patients with a history of multiple drug allergies or history of allergic reaction to an oligonucleotide or GalNAc

Patients with a history of intolerance to SC injection(s)

Patients with an anticipated or planned need for surgery during the study

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 judgement

E.5 End points

E.5.1

Primary end point(s)

Annualized Bleeding Rate (ABR) in the fitusiran efficacy period and the factor or BPA prophylaxis period

E.5.1.1

Timepoint(s) of evaluation of this end point

Through 13 months

E.5.2

Secondary end point(s)

Annualized spontaneous bleeding rate in the fitusiran efficacy period and the factor or BPA prophylaxis period

Annualized joint bleeding rate in the fitusiran efficacy period and the factor or BPA prophylaxis period

Change in Haem-A-QOL physical health score and total score in the fitusiran treatment period and the factor or BPA prophylaxis period

ABR in the fitusiran onset period

ABR in fitusiran treatment period

Annualized weight- adjusted consumption of factor/ BPA

E.5.2.1

Timepoint(s) of evaluation of this end point

Through 13 months

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

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

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

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

Yes

E.8.1.7.1

Other trial design description

switching study

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.8.2.3.1

Comparator description

Rescue therapy per Standard of Care

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

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

Ireland

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

Last Patient Last Visit (LPLV)

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

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)

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

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

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)

Patients who complete the study may be eligible for participation in an open-label extension study

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

2018-04-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-03-20

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2022-03-25

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