Clinical Trials Register

Summary
EudraCT Number:	2013-005324-41
Sponsor's Protocol Code Number:	ACT13739
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-07-03
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

Czechia - SUKL

A.2

EudraCT number

2013-005324-41

A.3

Full title of the trial

A Phase 2 Study to Evaluate the Safety, Pharmacodynamics, Pharmacokinetics, and Exploratory Efficacy of GZ/SAR402671 in Enzyme Replacement Therapy (ERT) Treatment-naïve Adult Male Patients Diagnosed with Fabry Disease

Klinické hodnocení 2. fáze hodnotící bezpečnost, farmakodynamiku, farmakokinetiku a předběžnou účinnost GZ/SAR402671 u dospělých mužů s Fabryho chorobou, kteří nebyli léčeni enzymatickou náhradní terapií (ERT)

A.3.1

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

Evaluate the Safety, Pharmacodynamics, Pharmacokinetics, and Exploratory Efficacy of GZ402671 in Treatment-naïve Adult Male Patients with Fabry Disease

A.4.1

Sponsor's protocol code number

ACT13739

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1152-1456

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	sanofi-aventis, s.r.o.
B.5.2	Functional name of contact point	www.sanofi-aventis.cz
B.5.3	Address:
B.5.3.1	Street Address	Evropská 846/176a
B.5.3.2	Town/ city	Praha 6
B.5.3.3	Post code	160 00
B.5.3.4	Country	Czech Republic
B.5.4	Telephone number	+420233 08 61 11
B.5.5	Fax number	+420233 08 62 24
B.5.6	E-mail	cz-info@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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.2	Product code	GZ402671 / SAR402671
D.3.4	Pharmaceutical form	Capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.1	CAS number	1401090-53-6
D.3.9.2	Current sponsor code	SAR402671 / GZ402671
D.3.9.3	Other descriptive name	Genz-682452-AA
D.3.9.4	EV Substance Code	SUB166602
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	4
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.2.5	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.3.2	Product code	GZ402671 / SAR402671
D.3.4	Pharmaceutical form	Capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.1	CAS number	1401090-53-6
D.3.9.2	Current sponsor code	SAR402671 (GZ402671)
D.3.9.3	Other descriptive name	Genz-682452-AA
D.3.9.4	EV Substance Code	SUB166602
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	15
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

Fabry disease

E.1.1.1

Medical condition in easily understood language

Fabry disease

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	17.1
E.1.2	Level	PT
E.1.2	Classification code	10016016
E.1.2	Term	Fabry's disease
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic disorders

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 safety, pharmacokinetics (PK), pharmacodynamics (PD), and exploratory efficacy of GZ402671 / SAR402671 in enzyme replacement therapy treatment-naïve adult male patients diagnosed with Fabry disease.

E.2.2

Secondary objectives of the trial

Not applicable

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

The patient is ≥18 years of age and <50 years of age.
The patient is male.
The patient has provided a signed informed consent.
The patient had a confirmed diagnosis of Fabry disease as documented by leukocyte α-Galactosidase A (αGAL) activity of <4 nmol/hr/mg leukocyte (preferred assay; results from a central laboratory) or plasma αGAL <1.5 nmol/hr/mL (results from a central laboratory).
The patient has a plasma globotriaosylsphingosine (lyso-GL3) ≥ 65 ng/mL.
The patient has never been treated with a Fabry disease-specific treatment.
If the patient is on renin-angiotensin-aldosterone system (RAAS) blockers and antidepressants, the dose should be stable (ie, prescribed dose and frequency) for at least the immediate 3 months prior to screening.

E.4

Principal exclusion criteria

The patient has an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m^2 using (Kidney Disease Epidemiology Collaboration) CKD-EPI.
The patient has a median urine protein/creatinine ratio (PCR) ≥0.5 g/g (median of 3 overnight urine collections. Collection of each of the 3 samples must occur between 4 and 7 days of each other, and all samples must be collected within a 21 day period). All 3 samples must be collected regardless of the results and results available prior to Day 1.
The patient had undergone a kidney transplant.
The patient has either active or a history of clinically significant organic disease (with the exception of the symptoms related to Fabry disease), including clinically significant cardiovascular, hepatic, pulmonary, hematologic, neurological or renal disease, or other medical condition, serious inter-current illness, or extenuating circumstances that, in the opinion of the Investigator, would preclude participation in the trial.
The patient has abnormal liver function (serum total bilirubin >the upper limit of normal, or serum alanine aminotransferase [ALT] and aspartate aminotransferase [AST] >2.0 times the upper limit of normal).
The patient has, according to World Health Organization (WHO) Grading a cortical cataract (COR) >one-quarter of the lens circumference (Grade COR-2) or a posterior subcapsular cataract (PSC) >2 mm (Grade PSC-2). Patients with nuclear cataracts are not excluded.
The patient is currently receiving potentially cataractogenic medications.
The patient has received strong or moderate inducers or inhibitors of Cytochrome P450 3A4 (CYP3A4) per Food and Drug Administration (FDA) classification within 14 days prior to enrolment or within 5 times the elimination half-life or PD half-life of the medication, whichever is longer.
The patient is scheduled for in-patient hospitalization, including elective surgery, during the study.
The patient has a positive result on any of the following tests: hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (anti-HCV) antibodies, anti-human immunodeficiency virus 1 and 2 antibodies (anti-HIV1 and anti-HIV2 Ab). Patients with a positive hepatitis B surface antibody (HBsAb) test with a history of prior hepatitis B immunization are eligible if other criteria are met (ie, negative tests for:
HBsAg, hepatitis B core antibody [HBcAb], and hepatitis C virus antibody [HCVAb]).
The patient has participated in a study involving an investigational drug within the past 30 days of the start of the trial.
The patient is unwilling to comply with the requirements of the protocol.
The patient is a sexually active man who is not willing to use 2 forms of birth control including a barrier method during the study.
The patient has history or ongoing clinically significant cardiac arrhythmia, defined as either atrial fibrillation, sustained or non-sustained ventricular tachycardia
The patient has any contraindication to magnetic resonance imaging (MRI).
The patient has one of the following central nervous system exclusion criteria:
Acute stroke, within 3 months of the screening visit.
History of seizures.

E.5 End points

E.5.1

Primary end point(s)

Change from baseline in globotriaosylceramide (GL-3) scores as evaluated by light microscopy (LM) in superficial skin capillary endothelium

E.5.1.1

Timepoint(s) of evaluation of this end point

26 weeks

E.5.2

Secondary end point(s)

30 weeks
1)Change from baseline in GL-3, lyso GL-3, and plasma glucosylceramide (GL-1)
2)Change from baselline in scores of GL-3 from other cell types in skin biopsy using LM
3)Urine GL-3 change from baseline

Up to 54 weeks
4) Characterization of the safety profile of GZ402671, including the frequency, duration, and severity of adverse events (AEs)

26 weeks
5) Assessment PK parameters – peak concetration (Cmax), Dose-Corrected Observed Plasma Trough Concentrations (Ctrough),and time to reach max concentration (tmax)
6) Assessment of PK parameters - terminal half-life (t1/2z), area under the concentration-time curve from 0 to 24 hours
(AUC0-24), and plasma clearance at steady state (CLss/F)
7) Assessment of PK parameters - volume of distribution at steady-state (Vss/F) and cumulated amount excreted in urine from 0 to 24 hours (Ae0-24)
8) Assessment of PK parameters- fraction of dose excreted in urine from 0 to 24 hours (Fe0-24) and renal clearance of the drug determined in 0 to 24 hours interval (CLr0-24)

E.5.2.1

Timepoint(s) of evaluation of this end point

30 weeks
1) 2) 3)

Up to 54 weeks
4)

26 weeks
5) 6) 7) 8)

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

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

Yes

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

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

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

Czech Republic

France

Poland

Russian Federation

United Kingdom

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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

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)

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)

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

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.4.2.2

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)

Eligible patients may enter an Extension Trial

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

2014-09-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-09-18

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-09-06

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IMP with orphan designation in the indication
Orphan Designation Number:
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