Clinical Trials Register

Summary
EudraCT Number:	2019-002375-34
Sponsor's Protocol Code Number:	EFC15299
National Competent Authority:	Portugal - INFARMED
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2019-12-03
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

Portugal - INFARMED

A.2

EudraCT number

2019-002375-34

A.3

Full title of the trial

A multicenter, multinational, randomized, double-blind, placebo-controlled study to assess the efficacy, pharmacodynamics, pharmacokinetics, safety, and tolerability of venglustat in late-onset GM2 gangliosidosis (Tay-Sachs disease and Sandhoff disease) together with a separate basket for juvenile/adolescent late-onset GM2 gangliosidosis and ultra-rare diseases within the same and similar glucosylceramide-based sphingolipid pathway

A.3.1

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

A multinational, randomized, double-blind, placebo-controlled study to assess the efficacy, pharmacodynamics, pharmacokinetics, and safety of venglustat in late-onset GM2

A.3.2

Name or abbreviated title of the trial where available

AMETHIST

A.4.1

Sponsor's protocol code number

EFC15299

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1197-7905

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

P/457/2020

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-Produtos Farmacêuticos, Lda
B.5.2	Functional name of contact point	Cristina Garcia
B.5.3	Address:
B.5.3.1	Street Address	Empreendimento Lagoas Park, Ed. 7, 3º piso
B.5.3.2	Town/ city	Porto Salvo
B.5.3.3	Post code	2740-244
B.5.3.4	Country	Portugal
B.5.4	Telephone number	+34600932546
B.5.5	Fax number	+34934895762
B.5.6	E-mail	es-reg-estudiosclinicos@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.3.1	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.3.8	INN - Proposed INN	Venglustat
D.3.9.1	CAS number	1401090-53-6
D.3.9.2	Current sponsor code	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	No
D.2.5.1	Orphan drug designation number
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	Yes
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Venglustat
D.3.9.1	CAS number	1401090-53-6
D.3.9.2	Current sponsor code	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	6
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: 3
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	Venglustat
D.3.2	Product code	GZ402671
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	Yes
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Venglustat
D.3.9.1	CAS number	1401090-53-6
D.3.9.2	Current sponsor code	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	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.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Tay-Sachs disease
Sandhoff disease

E.1.1.1

Medical condition in easily understood language

Tay-Sachs disease
Sandhoff disease

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	23.0
E.1.2	Level	LLT
E.1.2	Classification code	10043147
E.1.2	Term	Tay-Sachs disease
E.1.2	System Organ Class	100000004850

E.1.2 Medical condition or disease under investigation

E.1.2	Version	23.0
E.1.2	Level	LLT
E.1.2	Classification code	10081314
E.1.2	Term	Sandhoff disease
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

- Primary population: To assess the efficacy and pharmacodynamics (PD) of daily oral dosing of venglustat when administered over a 104-week period

- Secondary population: To assess PD response (plasma and CSF GL-1 biomarker and disease specific biomarkers) of venglustat when administered once daily over a 104-week period

E.2.2

Secondary objectives of the trial

Primary population (adult participants with late-onset GM2 gangliosidosis):
- To assess the effect of venglustat on selected performance test and scale over a 104-week period
- To determine the safety and tolerability of venglustat when administered orally once daily over a 104-week period
- To assess the pharmacokinetics (PK) of venglustat in plasma and cerebrospinal fluid (CSF)

Secondary population (participants with juvenile/adolescent late-onset GM2 gangliosidosis, GM1 gangliosidosis, saposin C deficiency, sialidosis type 1 or juvenile/adult galactosidosis):
- To assess the effect of venglustat on selected performance tests and scale over a 104-week period
- To determine the safety and tolerability of venglustat when administered once daily over a 104-week period
- To assess the PK of venglustat in plasma and CSF

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Primary population and adult secondary population: age ≥ 18 years
- Juvenile/adolescent secondary population: 2 ≥ age < 18 years with
weight ≥ 10 kg
- Participants with a diagnosis of late onset GM2 gangliosidosis (Tay-
Sachs disease and Sandhoff disease) caused by genetic β-
hexosaminidase deficiency resulting from mutations in the HEXA or
HEXB genes (primary population only); a secondary population will
enroll patients with diagnosis of juvenile/adolescent GM2 gangliosidosis,
GM1 gangliosidosis, saposin C deficiency, sialidosis type 1 or juvenile
adult galactosialidosis
- For primary population, the participant has the ability to perform the 9-
HPT at the screening visit in < = 240 seconds for the 2 consecutive trials
of the dominant hand and the 2 consecutive trials of the nondominant
hand.
- Participants with a history of seizures well controlled by medication
other than strong or moderate inducer or inhibitor of CYP3A4
- Participant is cooperative, able to ingest oral medication, willing to
travel to a study site (if applicable), and able to comply with all aspects
of the study, including all assessments, according to the Investigator's
judgement
- Signed written informed assent/consent
- Contraception for sexually active male participants or female patient;
not pregnant or breastfeeding; no sperm donating for male participant

E.4

Principal exclusion criteria

caused by β-hexosaminidase deficiency resulting from mutations in the
HEXA or HEXB genes and/or is without clinical features
- For primary population and participants with juvenile/adolescent late
onset GM2 gangliosidosis and GM1 gangliosidosis, the participant cannot
understand and perform all age-appropriate study assessments with the
exception of 25FWT and PROs.
- Relevant medical disorders that would compromise his/her safety
- Documented diagnosis of hepatitis B, C, human immunodeficiency virus
1 or 2
- World Health Organization (WHO) grade > 2 cortical cataract or a
grade > 2 posterior subcapsular cataract; patients with nuclear cataracts
will be accepted
- Participant who requires invasive ventilatory support
- Current treatment by anticoagulants, cataractogenic medications or
any medications that may worsen the vision of patient with cataract
- Previous treatment with substrate reduction therapy (SRT) within 3
months prior to study enrollment, strong or moderate inducers or
inhibitors of CYP3A4 within 14 days or 5 half-lives prior to enrollment.
This also includes the consumption of grapefruit, grapefruit juice or
grapefruit products within 72hrs prior to starting investigational
medicinal product (IMP) administration.
- Current participation in another study
- Use of investigational medicinal product (IMP) within 3 months or 5
half-lives prior to enrollment, whichever is longer, before study
enrollment (for N-acetyl-leucine, within 5 half-lives before study
enrollment).
- Liver enzymes (alanine aminotransferase [ALT]/aspartate
aminotransferase [AST]) or total bilirubin > 2 x the upper limite of
normal (ULN) at the time of screening unless the participant has the
diagnosis of Gilbert syndrome and maintains a level of bilirubin < 5
mg/dl and direct bilirubin < 20% (1 mg/dl) of total bilirubin level
- Renal insufficiency is defined by estimated glomerular filtration rate

E.5 End points

E.5.1

Primary end point(s)

1 - Change in cerebrospinal fluid (CSF) GM2 biomarker ; Percent change in CSF GM2 biomarker from baseline to Week 104 in primary population
2 - Change in the 9-hole pegboard test (9-HPT) ; Annualized rate of change in the 9-HPT from baseline to Week 104 in primary population
3 - Assessment of pharmacodynamic (PD) response in plasma and CSF:
- GL-1, GM1 biomarkers ; Concentration of GL-1 biomarker with pathway specific biomarker GM1 for GM1 gangliosidosis in secondary population
- GL-1, GM2 biomarkers ; Concentration of GL-1 with GM2 for GM2 gangliosidosis in secondary population
- GL-1, GM2, GM3 biomarkers ; Concentration of GL-1 with GM2, GM3 for sialidosis in secondary population
- GL-1, GM1, GM3 biomarkers ; Concentration of GL-1 with GM1, GM3 for galactosialidosis in secondary population
- GL-1 biomarker ; Concentration of GL-1 for saposin C deficiency in secondary population

E.5.1.1

Timepoint(s) of evaluation of this end point

1, 2, 3 : From baseline to Week 104

E.5.2

Secondary end point(s)

1 - Safety/tolerability: Adverse events ; Number of patients with adverse events
2 - Assessment of pharmacokinetic (PK) parameters in plasma: Cmax ; Maximum venglustat concentration (Cmax)
3 - Assessment of PK parameters in plasma: tmax ; Time to maximum venglustat concentration (tmax)
4 - Assessment of PK parameters in plasma: AUC0-24h ; Concentration versus time curve calculated using the trapezoidal method from time 0 to 24 hours (AUC0-24h)
5 - Assessment of PK parameters in plasma: plasma concentrations;Plasma venglustat concentration
6 - Assessment of PK parameters :CSF venglustat; CSF venglustat concentration
7 - Change in 25-foot walk test (FWT) ; Change in timed 25-FWT from baseline to Week 104 (in patients able to walk at baseline)
8 - Change in Friedreich's Ataxia Rating Scale (FARS) ; Change in FARS score from baseline to Week 104
9 - Change in 9-hole peg test (9-HPT) ; Annualized rate of change in the 9-HPT from baseline to Week 104 in secondary population

E.5.2.1

Timepoint(s) of evaluation of this end point

1, 5, 7,8,9 : From baseline to Week 104
6: Week 104
2,3,4: From baseline up to Week 12

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

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

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

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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

For secondary population: open-label treatment with venglustat only

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

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.8.5

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

Argentina

Brazil

Japan

United States

Austria

France

Spain

Czechia

Germany

Italy

Portugal

Russian Federation

Turkey

United Kingdom

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

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)

Yes

F.1.1.5.1

Number of subjects for this age range:

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)

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

104

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)

None

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

2019-12-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-05-25

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

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