Clinical Trials Register

Summary
EudraCT Number:	2019-002375-34
Sponsor's Protocol Code Number:	EFC15299
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:	2021-06-17
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

2019-002375-34

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

Studio multicentrico, internazionale, randomizzato, in doppio cieco, controllato con placebo volto a valutare l’efficacia, la farmacodinamica, la farmacocinetica, la sicurezza e la tollerabilità di venglustat nella gangliosidosi GM2 a esordio tardivo (malattia di Tay-Sachs e malattia di Sandhoff), insieme ad una coorte separata per la gangliosidosi GM2 giovanile/adolescenziale a esordio tardivo e per malattie ultra rare riconducibili ad alterazioni della stessa via metabolica, o similari, degli sfingolipidi a base di glucosilceramide

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

Studio internazionale, randomizzato, in doppio cieco, controllato con placebo per valutare l’efficacia, la farmacodinamica, la farmacocinetica e la sicurezza di venglustat nella GM2 a esordio tardivo

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

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 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	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	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.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	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.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	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
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

malattia di Tay-Sachs
malattia di Sandhoff (codice MedDRA PT 10081314, versione 21.1 non trovato a sistema: è stato quindi inserito il termine SOC 10010331, di cui il PT 10081314 fa parte)

E.1.1.1

Medical condition in easily understood language

Tay-Sachs disease
Sandhoff disease

malattia di Tay-Sachs
malattia di Sandhoff

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	10010331 - Congenital, familial and genetic disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	SOC
E.1.2	Classification code	10010331
E.1.2	Term	Congenital, familial and genetic disorders
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

- 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

- Popolazione primaria:
Valutare l’efficacia e la farmacodinamica (PD) del dosaggio orale giornaliero di venglustat somministrato in un periodo di 104 settimane
Popolazione secondaria:
• Valutare la risposta PD (biomarcatore GL-1 del plasma e del CSF e biomarcatori specifici della malattia) di venglustat somministrato una volta al giorno in un periodo di 104 settimane.

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.

Popolazione primaria (partecipanti adulti con gangliosidosi GM2 a esordio tardivo):
-Valutare l’effetto di venglustat sulla base dei test e delle scale delle prestazioni selezionati in un periodo di 104 settimane.
-valutare la sicurezza e la tollerabilità di venglustat quando somministrato per via orale una volta al giorno in un periodo di 104 settimane.
- valutare la farmacocinetica (PK) di Venglustat nel plasma e nel liquido cerebrospinale (CSF).
Popolazione secondaria (partecipanti con gangliosidosi GM2giovanile/adolescenziale a insorgenza tardiva, gangliosidosi GM1, deficit di saposina C, sialidosi di tipo 1 o galattosialidosi giovanile/adulta)
- Valutare l’effetto di venglustat sulla base dei test e delle scale delle prestazioni selezionati in un periodo di 104 settimane.
- valutare la sicurezza e la tollerabilità di venglustat quando somministrato per via orale una volta al giorno in un periodo di 104 settimane.
- la PK di Venglustat nel plasma e nel liquido cerebrospinale (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 ß-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 or chew and swallow 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.

-Popolazione primaria e popolazione secondaria adulta: età >/= 18 anni
-Bambini/adolescenti appartenenti alla popolazione secondaria: età compresa tra >/= 2 e < 18 anni con un peso >/= 10 kg
-Partecipanti con una diagnosi clinica di gangliosidosi GM2 a insorgenza tardiva (malattia di Tay-Sachs e malattia di Sandhoff) causata dal deficit di ß-esosaminidasi derivante da mutazioni nei geni HEXA o HEXB
(solo popolazione primaria); nella popolazione secondaria possono essere arruolati pazienti con diagnosi clinica di gangliosidosi GM2 giovanile/adolescenziale a insorgenza tardiva, gangliosidosi GM1, deficit di saposina C, sialidosi di tipo 1 o galattosialidosi giovanile/adulta.
Per la popolazione primaria, il partecipante ha la capacità di eseguire il test 9-HPT alla visita di screening in </= 240 secondi valutato in 2 tentativi consecutivi eseguiti con la mano dominante e in 2 tentativi consecutivi con la mano non dominante.
-Partecipante con un’anamnesi di crisi convulsive ben controllate con il farmaco appropriato, non classificato come induttore o inibitore forte o moderato dell’enzima CYP3A4
-Il partecipante è collaborativo, in grado di ingerire o masticare e deglutire farmaci orali, disposto a recarsi in un centro dello studio (se applicabile) e in grado di rispettare tutti gli impegni dello studio, comprese tutte le valutazioni, secondo il giudizio dello sperimentatore.
-Firma del consenso informato/assenso
-Contraccezione per partecipanti di sesso maschile o femminile sessualmente attivi; non incinta o in allattamento

E.4

Principal exclusion criteria

- Participant has clinical features of Tay-Sachs or Sandhoff disease, not caused by ß-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.
- 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
- 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 (eGFR) < 30 mL/min/1.73m2 at the screening visit

-Il partecipante presenta caratteristiche cliniche della malattia di Tay-Sachs o di Sandhoff, non dovuto a deficit di ß-esosaminidasi causato da mutazioni nei geni HEXA o HEXB e/o non presenta caratteristiche cliniche
Per la popolazione primaria e i partecipanti con gangliosidosi GM2 a insorgenza in età giovanile/adolescenziale e gangliosidosi GM1, il partecipante non è in grado di comprendere ed eseguire tutte le valutazioni dello studio appropriate all’età, ad eccezione del 25FWT.
-Disturbi medici clinicamente rilevanti che potrebbero compromettere la sua sicurezza.
-Diagnosi documentata di epatite B, epatite C, virus dell’immunodeficienza umana 1 o 2
-Secondo la classificazione dell’Organizzazione mondiale della sanità (OMS) il partecipante presenta una cataratta corticale > Grado 2 o una cataratta sottocapsulare posteriore > Grado 2. I partecipanti con cataratta nucleare non saranno esclusi.
-Il partecipante richiede l’uso di un supporto ventilatorio invasivo
-Il partecipante è sottoposto a trattamento in corso con anticoagulanti, farmaci catarattogenici o altri farmaci che potrebbero peggiorare la visione del paziente con cataratta.
-Precedenti trattamento con terapie di riduzione del substrato (SRT) nei 3 mesi precedenti l’arruolamento nello studio, induttori o inibitori, forti o moderati, dell’enzima CYP3A4 nei 14 giorni o nelle 5 emivite precedenti l’arruolamento nello studio.
-Attuale partecipazione a un altro studio interventistico sperimentale.
-Uso dell’IMP, nei 3 mesi o nelle 5 emivite prima dell'arruolamento nello studio, a seconda del periodo più lungo, (per N-acetil-leucina, entro 5 emivite prima dell'arruolamento nello studio
-Enzimi epatici (alanina aminotransferasi [ALT]/aspartato aminotransferasi [AST]) o bilirubina totale >2 volte il limite superiore della norma (ULN) al momento dello screening, a meno che il partecipante non presenti una diagnosi di sindrome di Gilbert e mantenga un livello di bilirubina totale <5 mg/dl e bilirubina diretta <1 mg/dl (20%) del livello di bilirubina totale.
Insufficienza renale definita dalla velocità di filtrazione glomerulare stimata < 30 ml/min/1,73 m2 alla visita di screening.

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.

1-Variazione del biomarcatore GM2 nel fluido cerebrospinale (CSF); variazione percentuale del biomarcatore GM2 nel liquido cerebrospinale (CSF) dal basale alla Settimana 104 nella popolazione primaria.
2-Variazione nel test dei 9 pioli (9-HPT): tasso annualizzato di variazione nel test dei 9 pioli (9-HPT) dal basale alla Settimana 104 nella popolazione primaria.
3-Valutazione della risposta farmacodinamica (PD) nel plasma e nel CSF:
- biomarcatori GL-1, GM1; Concentrazione del biomarcatore GL-1 con il biomarcatore GM1 specifico per il pathway per la gangliosidosi GM1 nella popolazione secondaria
- biomarcatori GL-1, GM2; Concentrazione di GL-1 con GM2 per la gangliosidosi GM2 nella popolazione secondaria
- biomarcatori GL-1, GM2, GM3; Concentrazione di GL-1 con GM2, GM3 per la sialidosi nella popolazione secondaria
- biomarcatori GL-1, GM1, GM3; Concentrazione di GL-1 con GM1, GM3 per la galactosialidosi nella popolazione secondaria
- biomarcatore GL-1; Concentrazione di GL-1 per il deficit di saposina C nella popolazione secondaria

E.5.1.1

Timepoint(s) of evaluation of this end point

1, 2, 3 : From baseline to Week 104.

1,2,3,: da basale alla settimana 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)
Assessment of PK parameters in plasma: tmax ; Time to maximum venglustat concentration (tmax)
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)
3 - Assessment of PK parameters in CSF: Cmax ; Maximum venglustat concentration (Cmax)
Assessment of PK parameters in CSF: tmax ; Time to maximum venglustat concentration (tmax)
Assessment of PK parameters in CSF: AUC0-24h ; Concentration versus time curve calculated using the trapezoidal method from time 0 to 24 hours (AUC0-24h)
4 - Change in 25-foot walk test (FWT) ; Change in timed 25-FWT from baseline to Week 104 (in patients able to walk at baseline)
5 - Change in Friedreich's Ataxia Rating Scale (FARS) ; Change in FARS score from baseline to Week 104
6 - Change in 9-hole peg test (9-HPT) ; Annualized rate of change in the 9-HPT from baseline to Week 104 in secondary population.

1. Sicurezza /tollerabilità: eventi avversi; Numero di pazienti con eventi avversi
2. Valutazione dei parametri di farmacocinetica (PK) nel plasma: Cmax; Concentrazione massima di venglustat (Cmax)
Valutazione dei parametri PK nel plasma: tmax; tempo alla concentrazione massima di venglustat (tmax)
Valutazione dei parametri PK nel plasma: AUC 0-24h; area sotto la concentrazione rispetto alla curva del tempo usando il metodo trapezoidale dal tempo 0 alle 24 ore (AUC 0-24h)
3. Valutazione dei parametri di farmacocinetica (PK) nel CSF: Cmax; Concentrazione massima di venglustat (Cmax)
Valutazione dei parametri PK nel CSF: tmax; tempo alla concentrazione massima di venglustat (tmax)
Valutazione dei parametri PK nel CSF: AUC 0-24h; area sotto la concentrazione rispetto alla curva del tempo usando il metodo trapezoidale dal tempo 0 alle 24 ore (AUC 0-24h)
4. Variazione nel 25FWT: Variazione nel 25FWT dal basale alla Settimana 104 (nei partecipanti in grado di camminare al basale)
5. Variazione nell’esame neurologico della scala FARS ; Variazione nell’esame neurologico della scala FARS dal basale alla Settimana 104
6. Variazione nel test 9-HPT; Tasso annualizzato di variazione nel test 9-HPT dal basale alla Settimana 104 nella popolazione secondaria

E.5.2.1

Timepoint(s) of evaluation of this end point

1,2,3,4,5,6: from baseline to week 104.

1,2,3,4,5,6: dal basale alla settimana 104.

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

per popolazione secondaria: trattamento in aperto con solo venglustat

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.8.4.1

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

Brazil

Japan

Russian Federation

Turkey

United States

Austria

France

Germany

Italy

Portugal

Spain

United Kingdom

Czechia

Argentina

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)

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

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 who complete the Week 110 assessments of the current study will be given the option to enroll in a long-term safety (LTS) follow-up study to assess safety and tolerability of venglustat.

Ai Partecipanti che completano la valutazione della settimana 110 del presente studio verrà data la possibilità di partecipare ad unoc studio di follow-up di sicurezza a lungo termine (LTS) per valutare la sicurezza e la tollerabilità di venglustat.

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

2019-12-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-03-04

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

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