Clinical Trials Register

Summary
EudraCT Number:	2019-000667-24
Sponsor's Protocol Code Number:	ST-920-201
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:	2021-09-23
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

2019-000667-24

A.3

Full title of the trial

A Phase I/II, Multicenter, Open-Label, SingleDose, Dose-Ranging Study to Assess the Safety and Tolerability of ST-920, an AAV2/6 Human Alpha Galactosidase A Gene Therapy in Subjects with Fabry Disease

Studio dose-ranging di fase I/II, multicentrico, in aperto, a dose singola per valutare la sicurezza e la tollerabilità di ST-920, una terapia genica con alfa-galattosidasi A umana AAV2/6 in soggetti affetti da malattia di Fabry

A.3.1

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

A Phase I/II Study to Assess the Safety and Tolerability of ST-920, an AAV2/6 Human Alpha Galactosidase A Gene Therapy, in Subjects with Fabry Disease

Studio di fase I/II, per valutare la sicurezza e la tollerabilità di ST-920, una terapia genica con alfa-galattosidasi A umana AAV2/6 in soggetti affetti da malattia di Fabry

A.3.2

Name or abbreviated title of the trial where available

STAAR

A.4.1

Sponsor's protocol code number

ST-920-201

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	Sangamo Therapeutics, Inc.
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	Sangamo Therapeutics, Inc.
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	Sangamo Therapeutics, Inc.
B.5.2	Functional name of contact point	ST-920-201 Information Desk
B.5.3	Address:
B.5.3.1	Street Address	7000 Marina Blvd.
B.5.3.2	Town/ city	Brisbane, CA
B.5.3.3	Post code	94005
B.5.3.4	Country	United States
B.5.4	Telephone number	+16282527495
B.5.5	Fax number	+15103238182
B.5.6	E-mail	clinicaltrials@sangamo.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/3/19/2241
D.3 Description of the IMP
D.3.1	Product name	Recombinant Adeno-associated virus 2/6 vector encoding the cDNA for human alpha galactosidase A
D.3.2	Product code	[ST-920]
D.3.4	Pharmaceutical form	Solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	ST-920
D.3.9.3	Other descriptive name	Adeno-associated virus serotype 2/6 encoding human alpha-galactosidase A cDNA
D.3.10	Strength
D.3.10.1	Concentration unit	Other
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	1
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
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)	Yes
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	Yes
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	Yes
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	Yes
D.2.1.1.1	Trade name	PARACETAMOLO DOC GENERICI - 1000 MG COMPRESSA 16 COMPRESSE
D.2.1.1.2	Name of the Marketing Authorisation holder	DOC GENERICI SRL
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	Paracetamolo
D.3.2	Product code	[Paracetamolo]
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PARACETAMOLO
D.3.9.2	Current sponsor code	-
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	650
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	Yes
D.2.1.1.1	Trade name	ALISERIN - 25 MG GRANULATO EFFERVESCENTE 20 BUSTINE
D.2.1.1.2	Name of the Marketing Authorisation holder	FARMAKOPEA S.P.A.
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	difenidramina cloridrato
D.3.2	Product code	[difenidramina cloridrato]
D.3.4	Pharmaceutical form	Effervescent granules
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	DIFENIDRAMINA CLORIDRATO
D.3.9.2	Current sponsor code	-
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	25 to 50
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: 4
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	Yes
D.2.1.1.1	Trade name	PREDNISONE DOC GENERICI - "5 MG COMPRESSE" 10 COMPRESSE IN BLISTER PVC-PVDC/ALU
D.2.1.1.2	Name of the Marketing Authorisation holder	DOC GENERICI SRL
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	Prednisone
D.3.2	Product code	[Prednisone]
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	PREDNISONE
D.3.9.2	Current sponsor code	-
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	60
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Fabry Disease (X-linked lysosomal storage disease)

Malattia di Fabry (malattia da accumulo lisosomiale legata al cromosoma X)

E.1.1.1

Medical condition in easily understood language

Fabry Disease

Malattia di Fabry

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	20.0
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 and tolerability of ST-920

Valutare la sicurezza e la tollerabilità di ST-920

E.2.2

Secondary objectives of the trial

•To assess a-Gal A activity and the presence of its substrates in plasma over time
•To assess impact of ST-920 on ERT administration required for subjects on ERT
•To assess the impact of ST-920 on renal function
•To assess the impact of ST-920 on cardiac function and left ventricular hypertrophy
•To evaluate ST-920 vector DNA shedding over time
Exploratory Objectives:
• To assess clinical impact of ST-920 on Fabry disease
• To assess the a-Gal activity overtime in skin and leukocytes
• To assess the presence of Gb3 inclusion levels substrates in skin in ERT-naïve and ERT-pseudo-naïve subjects (defined as not having received ERT treatment during the 6 months prior to consent)
• To assess the presence of a-Gal A substrates in urine for all subjects over time
• To assess immune response to AAV2/6
• To assess immune response to a-Gal A
• To assess the impact of ST-920 on substrate deposition in the kidney (via renal biopsy)in ERT-naïve and ERT pseudo-naïve subjects

Valutare l’attività di a-Gal A e la presenza dei suoi substrati nel plasma nel tempo
Valutare l’impatto di ST-920 sulla somministrazione dell’ERT richiesta per i soggetti sottoposti a ERT
Valutare l’impatto di ST-920 sulla funzionalità renale
Valutare l’impatto di ST-920 sulla funzionalità cardiaca e sull’ipertrofia ventricolare sinistra
Valutare la diffusione del DNA vettoriale di ST-920 nel tempo
Obiettivi esplorativi:
Valutare l’impatto clinico di ST-920 sulla malattia di Fabry
Valutare l’attività di a-Gal A nel tempo nella cute e nei leucociti
Valutare la presenza di livelli di inclusione di Gb3 nella cute in soggetti naïve all’ERT e pseudo-naïve all’ERT
Valutare la presenza di substrati di a-Gal A nelle urine per tutti i soggetti nel tempo
Valutare la risposta immunitaria ad AAV2/6
Valutare la risposta immunitaria ad a-Gal A
Valutare l’impatto di ST-920 sulla deposizione di substrato nel rene (mediante biopsia renale) in soggetti naïve all’ERT e pseudo-naïve all’ERT

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Subjects must meet all of the following criteria to be included in the study:
1. >=18 years of age
2. Signed, written informed consent
3. Diagnosis of Fabry disease
4. One or more of the following symptoms: i) cornea verticillata, ii) acroparesthesia, iii) anhidrosis, iv) angiokeratoma
5. Subjects who are on ERT or are ERT-naïve or are ERT-pseudo-naïve (defined as not having received ERT treatment in the 6 months prior to consent). For subjects receiving ERT, ERT must have been administered at a stable dose for at least 6 months (defined as not having missed more than 3 doses of ERT during the 6 months prior to consent) and regimen (14 days ± 3 days for at least 3 months prior to screening); except for Cohort 3d (see inclusion criterion 8),who must have been on ERT for at least the past year prior to screening.
6. Male subjects must agree to use an effective form of contraception (e.g., sexual abstinence, documented vasectomy, condom) and refrain from sperm donation from the time of ST-920 administration until a minimum of 3 consecutive semen samples are negative for AAV2/6 after administration of ST-920 and a minimum of 90 days after ST-920 administration.
7. Female subjects from menarche until becoming post-menopausal or permanently sterile must have a negative serum pregnancy test at screening and must agree to use a highly effective contraception method from screening through the end of the study. Highly effective contraception in females includes:
• combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal or transdermal)
• progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable or implantable)
• intrauterine device (IUD)
• intrauterine hormone-releasing system (IUS)
• bilateral tubal occlusion or vasectomized partner
• sexual abstinence

AND
FOR OTHERS INCLUSION CRITERIA PLEASE REFERS TO STUDY PROTOCOL

I soggetti che incontrano tutti i seguenti criteri di inclusione sarannò inclusi nello studio:
1. Età>=18 anni
2. Consenso informato scritto firmato
3. Diagnosi della malattia di Fabry
4. Uno o più dei seguenti sintomi: i) cornea verticillata, ii) acroparestesia, iii) anidrosi, iv) angiocheratoma
5. Soggetti in terapia con ERT o naïve all’ERT o pseudo-naïve all’ERT (definiti come soggetti che non hanno ricevuto il trattamento con ERT nei 6 mesi precedenti il consenso). Per i soggetti che ricevono ERT, la ERT deve essere stata somministrata a una dose stabile per almeno 6 mesi (definita come non aver saltato più di 3 dosi di ERT durante i 6 mesi precedenti il consenso) e regime stabile (14 giorni ±3 giorni per almeno 3 mesi prima dello screening), fatta eccezione per la Coorte 3d (vedere il criterio di inclusione 8), i cui soggetti devono essere stati sottoposti a ERT almeno nell’ultimo anno che precede lo screening.
6. I soggetti di sesso maschile devono accettare di utilizzare un metodo contraccettivo efficace (ad es. astinenza sessuale, vasectomia documentata, preservativo) ed astenersi dalla donazione di sperma dal momento della somministrazione di ST-920 fino a quando un minimo di 3 campioni consecutivi di liquido seminale non risultino negativi per AAV2/6 dopo la somministrazione di ST-920 e un minimo di 90 giorni dopo la somministrazione di ST-920.
7. I soggetti di sesso femminile dal menarca fino all’ingresso nella fase post-menopausa o fino a quando diventano permanentemente sterili devono risultare negativi a un test di gravidanza sul siero allo screening e devono accettare di utilizzare un metodo contraccettivo altamente efficace dallo screening fino alla fine dello studio. I metodi contraccettivi altamente efficaci comprendono:
• contraccettivi ormonali (orali, intravaginali o transdermici) combinati (contenenti estrogeni e progestinici);
• contraccettivo ormonale contenente solo progestinici (orale, iniettabile, impiantabile) associato a inibizione dell’ovulazione;
• dispositivo intrauterino (IUD);
• dispositivo intrauterino a rilascio di ormoni (IUS);
• occlusione tubarica bilaterale o partner vasectomizzato;
• astinenza sessuale.

PER GLI ALTRI CRITERI DI INCLUSIONE FARE RIFERIMENTO AL PROTOCOLLO DI STUDIO

E.4

Principal exclusion criteria

Subjects who meet any of the following criteria will be excluded from participating in the study:

1. Known to be unresponsive to ERT in the opinion of the Site Investigator and Medical Monitor (e.g., no documented substrate level decrease on ERT)
2. Current treatment with migalastat (Galafold™) or prior treatment within 3 months of informed consent
3. Positive neutralizing antibodies to AAV6
4. Intercurrent illness expected to impair evaluation of safety or efficacy during the observation period of the study in the opinion of the Site Investigator or Medical Monitor
5. eGFR <= 40 ml/min/1.73m2
6. Active infection with hepatitis A virus (HAV RNA positive), active or occult hepatitis B virus infection (positive HBV-DNA or anti-HBc positive), active infection with hepatitis C virus (HCV RNA positive), infection with the human immunodeficiency virus (HIV) as measured by quantitative polymerase chain reaction (qPCR) or active or latent infection with tuberculosis (TB) measured by quantiferon test
7. Breastfeeding at screening or planning to become pregnant (self or partner) or breastfeed during required period of contraception.
8. History of liver disease such as clinically significant steatosis, fibrosis, non-alcoholic steatohepatitis (NASH) and cirrhosis, biliary disease within
6 months of informed consent; except for Gilbert's syndrome
9. Elevated circulating serum AFP
10. For subjects receiving ERT, recent or recurrent hypersensitivity reaction manifested by significant infusion reaction to ERT treatment within 6 months prior to consent, in the opinion of the Site Investigator and Medical Monitor

FOR OTHERS EXCLUSION CRITERIA PLEASE REFERS TO STUDY PROTOCOL

I soggetti che incontrano uno dei seguenti criteri di esclusione saranno esclusi dallo studio:

1.Non responsività nota all’ERT secondo il parere dello sperimentatore del centro e del responsabile del monitoraggio medico (ad es. nessuna diminuzione documentata del livello di substrato durante l’ERT)
2.Trattamento attuale con migalastat (Galafold™) o precedente trattamento entro 3 mesi dal consenso informato
3.Positività agli anticorpi neutralizzanti per AAV6
4.Malattia intercorrente che ci si aspetta possa compromettere la valutazione della sicurezza o dell’efficacia durante il periodo di osservazione dello studio a giudizio dello sperimentatore del centro o del responsabile del monitoraggio medico
5.eGFR <=40 ml/min/1,73 m2
6.Infezione attiva da virus dell’epatite A (positività per l’RNA di HAV), infezione attiva od occulta da virus dell’epatite B (positività per HBV-DNA o positività per gli anticorpi anti-HBc), infezione attiva da virus dell’epatite C (positività per l’RNA di HCV), infezione da virus dell’immunodeficienza umana (HIV) misurata mediante reazione a catena della polimerasi quantitativa (qPCR) o infezione attiva o latente con tubercolosi (TB) misurata mediante test quantiferon
7.Allattamento al seno allo screening o intenzione di iniziare una gravidanza (da parte del soggetto stesso o della sua partner) o allattamento al seno durante il periodo di contraccezione richiesto
8.Anamnesi di malattia epatica come steatosi clinicamente significativa, fibrosi, steatoepatite non alcolica (NASH), cirrosi e malattia biliare entro 6 mesi dal consenso informato, fatta eccezione per la sindrome di Gilbert
9.Livelli elevati di AFP sierica circolante
10.Per i soggetti che ricevono ERT, reazione di ipersensibilità recente o ricorrente manifestata da una significativa reazione da infusione al trattamento con ERT nei 6 mesi precedenti il consenso, a giudizio dello sperimentatore del centro e del responsabile del monitoraggio medico.

PER GLI ALTRI CRITERI DI ESCLUSIONE FARE RIFERIMENTO AL PROTOCOLLO DI STUDIO

E.5 End points

E.5.1

Primary end point(s)

• Incidence of treatment-emergent adverse events (TEAEs)

Additional safety evaluations will include:

o Routine hematology, chemistry, and liver tests, vital signs, ECG and ECHO
o Serial alpha fetoprotein (AFP) testing and MRI of liver (or equivalent imaging modality) to monitor for any liver mass

• Incidenza di eventi avversi emergenti dal trattamento (TEAE)

Ulteriori valutazioni di sicurezza includeranno:

o Esami ematologici, chimici ed epatici di routine, segni vitali, elettrocardiogramma (ECG) ed ecocardiogramma (ECO)
o Test seriali dell’alfa fetoproteina (AFP) e risonanza magnetica per immagini (RMI) del fegato (o modalità di diagnostica per immagini equivalente) per monitorare la massa epatica

E.5.1.1

Timepoint(s) of evaluation of this end point

-AE Assessment: Screening, Baseline(BL), Day 1, 2, 8 , Weeks (Wks) 2, 4, 6, 8, 12, 16, 20, 24, 28, 32,36, 40, 44, 48, 52 (EOS) & Early Termination Visit (ETV)
-Clinical laboratory tests: Screening, BL, Day 1, 2, Weeks 2, 4, 6, 8, 12, 16, 20, 24, 36, 52 & ETV
-Liver Panel: Screening, BL, twice weekly during the first 20 weeks after ST-920 infusion while the subject is on prednisone or other equipotent steroid, Weekly for 4 Wks (Wks 21, 22, 23, 24 [±2 days]) following discontinuation of immunosuppression & then monthly thereafter
-Vital Signs: Screening, BL, Day 1, 2, 8, Wks 2, 4, 6, 8, 12, 16, 20, 24, 36, 52 & ETV
-ECG: Screening,BL, Day 8, Weeks 24, 52 & ETV
-ECHO: Screening, EOS & ETV
-AFP testing: Screening, Wks 4, 8, 12, 24, 52 & ETV
-MRI of liver: Screening, Wks 24, 52 & ETV

- EA:Screening, Baseline, Giorni 1,2,8, Settimane 2, 4, 6, 8, 12, 16, 20, 24, 28, 32,36, 40, 44, 48, 52 (EOS) e ETV
- Esami clinici di laboratorio: Screening, , Baseline, Giorni 1, 2, Settimane 2, 4, 6, 8, 12, 16, 20, 24, 36, 52 e ETV
- Esami epatici: Screening, BL, due volte a settimana per le prime 20 settimane post infusione di ST-920 (durante trattamento del paziente con steroidi), settimanalmente per 4 Settimane (21, 22, 23, 24 [±2 giorni]) dopo interruzione immunosoppressione e poi mensilmente;
- Segni vitali:Screening, BL, Giorni 1, 2, 8, Settimane 2, 4, 6, 8, 12, 16, 20, 24, 36, 52 e ETV
- ECG:Screening,BL, Giorni 8, Settimane 24, 52 e ETV
- ECO: Screening, EOS e ETV
- AFP: Screening, Settimane 4, 8, 12, 24, 52 e ETV
- RMI del fegato: Screening, Settimane 24, 52 e ETV

E.5.2

Secondary end point(s)

• Change from baseline at specific time points over the 1-year study period in:
o a-Gal A activity in plasma
o Gb3 and/or lyso-Gb3 levels in plasma

• Change from baseline at specific time points over the 1-year study period in:
o Frequency of ERT infusion
o Estimated glomerular filtration rate (eGFR) using the CKD-EPI formula
o Ejection fraction, global longitudinal strain, l Left ventricular mass index (LVMI), left ventricular systolic function measured by cardiac magnetic resonance imaging (CMR)
• ST-920 vector clearance measured by level of vector genome in blood (plasma), saliva, urine, stool, and semen

Exploratory Endpoints:
• Change from baseline at specific time points over the 1-year study period in:
o Late gadolinium enhancement (LGE), native myocardial T1 values and T2 mapping measured by cardiac MRI
o Functional capacity evaluated by maximum oxygen consumption (VO2 max) during cardiopulmonary testing
o High sensitivity Troponin T, N-terminal pro-hormone B-type natriuretic peptide (NT-proBNP) and microRNA assay
o Minnesota Living With Heart Failure Questionnaire (MLHF-Q) summary score
o Urine protein to creatinine ratio (UPCR) and urine albumin to creatinine ratio (UACR)
o Biomarkers of renal function in urine
o Neuropathic pain measured by the Brief Pain Inventory (BPI)
o Frequency of pain medication use
o Gastrointestinal (GI) symptoms measured by the GI symptoms rating scale
o Mainz Severity Score Index (MSSI)
o Quality of life (QOL) patient-reported outcome measured by the SF 36 questionnaire
o a-Gal A activity measured in skin and leukocytes
o Gb3 inclusion levels measured in skin in ERT-naïve and ERT-pseudonaïve subjects
o Gb3 and/or lyso-Gb3 levels in urine for all subjects over time
• Measurement of antibodies to AAV2/6
• Assessment of cell mediated immune response to AAV2/6
• Measurement of antibodies to a-Gal A
• Substrate deposition in the kidney (assessed by renal biopsy) in ERT naïve and ERT-pseudo-naïve subjects

•Variazione rispetto al valore basale in punti temporali specifici durante il periodo di studio di 1 anno in termini di:
oAttività di a-Gal A nel plasma
oLivelli di Gb3 e/o lyso-Gb3 nel plasma
•Variazione rispetto al valore basale in punti temporali specifici durante il periodo di studio di 1 anno in termini di:
oFrequenza dell’infusione di ERTVariazione rispetto al valore basale in punti temporali specifici durante il periodo di studio di 1 anno in termini di:
oVelocità di filtrazione glomerulare stimata (eGFR) utilizzando la formula di Collaborazione epidemiologica per la malattia renale cronica (CKD-EPI)

Endpoint esplorativi:
• Variazione rispetto al valore basale in punti temporali specifici durante il periodo di studio di 1 anno in termini di:
o Acquisizione tardiva di gadolinio (LGE), valori T1 nativi del tessuto miocardico e mappatura T2 misurati mediante RMI cardiaca
o Capacità funzionale valutata in base al consumo massimo di ossigeno (VO2 max) durante il test cardiopolmonare
o Troponina T ad alta sensibilità, frammento N-terminale del pro-peptide natriuretico di tipo B (NT-proBNP) e test del microRNA
o Punteggio riepilogativo del Questionario Minnesota sulla vita con insufficienza cardiaca (MLHF-Q)
o Rapporto proteine/creatinina nelle urine (UPCR) e rapporto albumina/creatinina nelle urine (UACR)
o Biomarcatori della funzione renale nelle urine
o Dolore neuropatico misurato mediante il questionario breve sul dolore (BPI)
o Frequenza di utilizzo di antidolorifici
o Sintomi gastrointestinali (GI) misurati mediante la scala di valutazione dei sintomi GI
o Indice del punteggio di gravità di Mainz (MSSI)
o Esito riferito dal paziente sulla qualità della vita (QOL) misurato mediante il questionario con Modulo breve a 36 voci (SF-36)
o Attività di a-Gal A misurata nella cute e nei leucociti
o Livelli di inclusione di Gb3 misurati nella cute in soggetti naïve all’ERT e pseudo-naïve all’ERT
o Livelli di Gb3 e/o lyso-Gb3 nelle urine per tutti i soggetti nel tempo
o Misurazione degli anticorpi anti AAV2/6
o Valutazione della risposta immunitaria cellulo-mediata ad AAV2/6
o Misurazione degli anticorpi anti-a-Gal A
o Deposito di substrato nel rene (valutato mediante biopsia renale) in soggetti naïve all’ERT e pseudo-naïve all’ERT

E.5.2.1

Timepoint(s) of evaluation of this end point

-a-Gal A, Gb3 &/or Lyso-Gb3 levels: Twice weekly during the first 20 wks after ST-920 infusion, then week 24, 28, 32, 36,40, 44, 48, 52 & ETV
-ERT administration log: Before & after ST-920 infusion (All timepoints except day 2)
-eGFR: Screening, BL, Day 8, Wk 4, 8,12,16,20,24,28,32,36,40,44,48,52 & ETV
-AAV2/6 clearance: BL, Day 8,Wk 2,4,8,12,16,20,24,36,52
Exploratory:
Cardiac MRI, GI Symptoms rating scale, MSSI, QOL: BL,Wk 24,52 &ETV
Protein & albumin to creatinine ratio in urine, Neuropathic pain: BL,Wk 12,24,36,52 &ETV
Frequency of pain medication use: All intervals except Day 1,2& 8 AAV Immunogenicity: BL,Wk 4,12,24,36,52(Additional samples when liver toxicity is suspected)
Immune response to a-Gal A: Screening,BL,Wk 4,8,12,16,24,36,52&ETV Renal Biopsy:BL &Wk

-Livelli di a-Gal A, Gb3 &/or Lyso-Gb3 : Due volte alla settimana per le prime 20 settimane dopo infusione di ST-920, poi Settimane 24, 28, 32, 36,40, 44, 48, 52 e ETV
-Log sulla somministrazione dell' ERT: Prima e dopo infusione di ST-920 (sempre eccetto giorno 2)
-eGFR: Screening, BL, Giorno 8, Settimane 4, 8,12,16,20,24,28,32,36,40,44,48,52 e ETV
-clearance di AAV2/6 : BL, Giorno 8,Settimane 2,4,8,12,16,20,24,36,52

Per i tempi di rilevazione degli endpoints esplorativi, fare riferimento alla sezione in inglese.

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

Yes

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)

Yes

E.7.1.1

First administration to humans

Yes

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

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

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

Yes

E.8.2.3.1

Comparator description

NA: studio non controllato

NA: not controlled study

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

Australia

Canada

Taiwan

United States

Germany

Italy

United Kingdom

E.8.7

Trial has a data monitoring committee

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 (last visit las subject)

LVLS (Ultima visita dell'ultimo soggetto)

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

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)

Upon completion of this study, subjects will be encouraged to participate in a separate long-term follow-up study for at least 5 years from infusion to monitor the long term safety of the study treatment.

Al termine di questo studio, i soggetti saranno incoraggiati a partecipare a uno studio di follow-up a lungo termine separato per almeno 5 anni dall'infusione per monitorare la sicurezza a lungo termine del trattamento in studio.

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

2022-03-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-03-01

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

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Orphan Designation Number:
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