Clinical Trials Register

Summary
EudraCT Number:	2014-002550-39
Sponsor's Protocol Code Number:	PDY13949
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2016-04-25
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

Germany - BfArM

A.2

EudraCT number

2014-002550-39

A.3

Full title of the trial

4-part, open-label, multicenter, multinational study of the
safety, tolerability, pharmacokinetics, pharmacodynamic, and exploratory
efficacy of venglustat in combination with Cerezyme in adult patients with
Gaucher disease Type 3 with venglustat monotherapy extension

A.3.1

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

Venglustat in Combination with Cerezyme in Adult Patients with Gaucher
Disease Type 3 with venglustat monotherapy extension

A.3.2

Name or abbreviated title of the trial where available

LEAP

A.4.1

Sponsor's protocol code number

PDY13949

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1156-4278

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 Deutschland GmbH
B.5.2	Functional name of contact point
B.5.3.4	Country	Germany
B.5.6	E-mail	medinfo.de@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	EMA/OD/152/14
D.3 Description of the IMP
D.3.1	Product name	Venglustat
D.3.2	Product code	GZ402671
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	SAR402671A / GZ402671
D.3.9.3	Other descriptive name	Genz-682452-AU
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.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	Yes
D.2.5.1	Orphan drug designation number	EMA/OD/152/14
D.3 Description of the IMP
D.3.1	Product name	Venglustat
D.3.2	Product code	GZ402671
D.3.4	Pharmaceutical form	Tablet
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	SAR402671A / GZ402671
D.3.9.3	Other descriptive name	Genz-682452-AU
D.3.9.4	EV Substance Code	SUB166602
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	2
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

Gaucher disease

E.1.1.1

Medical condition in easily understood language

Gaucher 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	24.1
E.1.2	Level	PT
E.1.2	Classification code	10075699
E.1.2	Term	Gaucher's disease type III
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	24.1
E.1.2	Level	PT
E.1.2	Classification code	10075697
E.1.2	Term	Gaucher's disease type I
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

Part 1:
-Evaluate central nervous system (CNS) biomarkers in adult Gaucher disease (GD) type 3 that distinguish GD3 from adult Gaucher disease type 1 (GD1) patients.
-Screen adult GD3 patients who qualify for treatment with
venglustat in Parts 2,3 and Part 4

Part 2 and 3: Combination treatment phases
-Evaluate short-term (Part 2) and long-term (Part 3) safety and
tolerability of GZ/SAR402671 in combination with Cerezyme in adult GD3 patients.
-Evaluate the change in cerebrospinal fluid (CSF) CNS biomarkers (glucosylceramide [GL-1] and lyso-glucosylceramide [lyso-GL1]) from adult GD3 patients receiving GZ/SAR402671 in combination with Cerezyme (Part 2 only).
Part 4: Extended treatment phase with monotherapy
- Evaluate safety and tolerability of venglustat monotherapy in adult
GD3 patients who have remained systemically stable on venglustat in
combination with Cerezyme

E.2.2

Secondary objectives of the trial

Parts 2 and 3: Combination treatment phases
-Evaluate the pharmacokinetics of GZ/SAR402671 in adult GD3 patients (Part2).
-Explore the efficacy of GZ/SAR402671 in combination with Cerezyme in infiltrative lung disease (IDL) in adult GD3 patients (Part 2 and 3).
-Explore the efficacy of GZ/SAR402671 in combination with Cerezyme in systemic disease in adult GD3 patients (Part 2 and 3).
-Explore the efficacy of GZ/SAR402671 in combination with Cerezyme in neurological function and on exploratory CSF biomarkers in adult GD3 patients (Part 2 and 3).
- Explore plasma biomarkers (lyso-GL-1 and GL-1) in adult GD3 patients
- Explore CSF biomarkers other than lyso-GL-1 and GL-1 in adult GD3
patients (Part 2 only)
Part 4: Extended treatment phase with monotherapy
- Explore the efficacy of venglustat in systemic disease in adult GD3
patients
- Explore the efficacy of venglustat on neurological function in adult GD3
patients
- Explore plasma biomarkers (lyso-GL-1 and GL-1) in adult GD3 patients

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

-The patient must provide written informed consent prior to any studyrelated procedures being performed.
-Has a clinical diagnosis of Gaucher Disease Type 1 (GD1) or Gaucher Disease Type 3 GD3 and documented deficiency of acid beta-glucosidase activity.
-The patient has received treatment with enzyme repalcement therapy for at least 3 years. For at least 6 months prior to enrollment, the Patient has received Cerezyme at a stable monthly dose and must continue at the same monthly dose during the study.
-The patient has reached Gaucher disease therapeutic goals defined as all of the following to be eligible for this study:
-Hemoglobin level of ≥11.0 g/dL for females and ≥12.0 g/dL for males.
-Platelet count ≥100 000/mm^3.
-Spleen volume <10 multiples of normal (MN)MN), or total splenectomy (provided the splenectomy occurred >3 years prior to randomization).
-Liver volume <1.5 MN.
-No bone crisis and free of symptomatic bone disease such as bone pain attributable to osteonecrosis and/or pathological fractures within 3 months prior to screening.
- The patient has maintained GD therapeutic goals defined as all of the following to be eligible for entering Part 4 of this study:
- Hemoglobin level of ≥11.0 g/dL for females and ≥12.0 g/dL for males
- Platelet count ≥100,000/mm3
- Spleen volume <10 multiples of normal (MN), or total splenectomy
- Liver volume <1.5 MN
- No bone crisis and free of symptomatic bone disease such as bone pain attributable to osteonecrosis and/or pathological fractures within 3 months prior to entering Part 4
- The patient, if female and of childbearing potential must have a negative pregnancy test (urine beta-human chorionic gonadotropin [β-hCG]) at baseline.
-If the patient has a history of seizures, except for myoclonic seizures, they are well controlled under appropriate medication not identified as a strong or moderate inducer or inhibitor of CYP3A.
Adult GD1 cohort only:
-GD1 patient is ≥18 and ≤40 years of age.
Adult GD3 cohort only:
-GD3 patient is ≥18 years of age.
-The patient is willing to abstain from consumption of grapefruit, grapefruit juice, or grapefruit containing products for 72 hours prior to administration of the first dose of GZ/SAR402671 and for the duration of the 156 week treatment period.
-Oculomotor apraxia characterized by a horizontal saccade abnormality.
-Cerezyme treatment every 2 weeks (minimum dose 30 U/kg every 2 weeks).
-Females patients of childbearing potential and males patients must be willing to practice true abstinence in line with their preferred and usual lifestyle, or use 2 acceptable effective methods of contraception for the duration of the study and for at least 6 weeks for females and 90 days for males following their last dose of study drug.

E.4

Principal exclusion criteria

-Substrate reduction therapy or chaperone therapy for GD within 6 months prior to enrollment.
-The patient has had a partial or total splenectomy within 3 years Prior to randomization.
-The patient is blood transfusion-dependent.
-Prior esophageal varices or liver infarction or current liver enzymes (alanine aminotransferase [ALT]/aspartate aminotransferase [AST]) or total bilirubin >2 times the upper limit of normal, unless the patient has a diagnosis of Gilbert Syndrome.
-Clinically significant congenital cardiac defect, coronary artery disease, valve disease or left sided heart failure; clinically significant arrhythmias or conduction defect.
-The patient has any clinically significant disease, other than GD, including cardiovascular, renal, hepatic, gastrointestinal, pulmonary, neurologic, endocrine, metabolic (eg, hypokalemia, hypomagnesemia), or psychiatric disease, other medical conditions, or serious intercurrent illnesses that may preclude participation.
-The patient has received an investigational product within 30 days Prior to enrollment.
-The patient has a history of cancer, with the exception of basal cell carcinoma.
-The patient has myoclonic seizures.
-The patient is pregnant or lactating.
-The patient has, according to World Health Organization (WHO) Grading, a cortical cataract >onequarter of the lens circumference (Grade cortical cataract-2) or a posterior subcapsular cataract >2 mm (Grade posterior subcapsular cataract-2). Patients with nuclear cataracts will not be excluded.
-The patient requires use of invasive ventilatory support.
-The patient requires use of noninvasive ventilator support while awake for longer than 12 hours daily.
-The patient is unable to receive treatment with Cerezyme due to a known hypersensitivity or is unwilling to receive Cerezyme Treatment every 2 weeks.
-The patient is currently receiving potentially cataractogenic medications as listed in Section 8.8.2.
-The patient has received strong or moderate inducers or inhibitors of Cytochrome p450 Isoform 3A within 30 days or 5 half-lives from screening, whichever is longer, prior to enrolment in Part 2. This also includes the consumption of grapefruit, grapefruit juice, or Grapefruit containing products within 72 hours of starting GZ/SAR402671 administration in Parts 2 and 3.
-The patient is scheduled for in-patient hospitalization including elective surgery, during the study.
-Has had a major organ transplant (eg, bone marrow or liver).
-The patient, in the opinion of the Investigator, is unable to adhere to the requirements of the study or unable to undergo study assessments (e.g., contraindications for magnetic resonance imaging).

E.5 End points

E.5.1

Primary end point(s)

1) Number of patients with adverse events
2) Assessment of pharmacodynamic (PD) parameter: Lysoglucosylceramide
(lyso-GL1) and glucosylceramide (GL-1) in
cerebrospinal fluid (CSF) ; Change from baseline in CSF lyso-GL1 and GL1

E.5.1.1

Timepoint(s) of evaluation of this end point

1 - From screening up to end of study, up to approximately 8.7 years

2 - From screening through Week 52

E.5.2

Secondary end point(s)

1 - Assessment of pharmacodynamic (PD) parameter: Lysoglucosylceramide
(lyso-GL1) and glucosylceramide (GL-1) in plasma ;
Change from baseline in plasma lyso-GL1 and GL1
2 - Assessment of plasma pharmacokinetic parameter: Cmax ; Plasma
maximum concentration (Cmax)
3 - Assessment of plasma pharmacokinetic parameter: Tmax ; Plasma
time at Cmax (Tmax)
4 - Assessment of plasma pharmacokinetic parameter: AUC ;Plasma area
under the curve (AUC)
5 - Assessment of plasma pharmacokinetic parameter: Ctrough ; Plasma
trough concentration (Ctrough)
6 - Assessment of CSF pharmacokinetic parameter: Cmax ; CSF maximum
concentration (Cmax)
7 - Assessment of pharmacokinetic parameter: CSF time at Cmax (Tmax)
8 - Assessment of pharmacokinetic parameter: CSF area under the curve
(AUC)

E.5.2.1

Timepoint(s) of evaluation of this end point

1 - From screening up to end of study, up to approximately 8.7 years
2, 3, 4, 6, 7, 8 - Day 1, Week 4, Week 26, and Week 52
5 - Weeks 12 and 39 (Part 2), and on Weeks 78, 104, and 156 (for Part
3)

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

Japan

United Kingdom

United States

Germany

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

Yes

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

Yes

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)

Eligible patients may enter an extension trial. Patients will remain on Cerezyme as standard treatment of care

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

2016-09-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-10-20

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

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