Clinical Trials Register

Summary
EudraCT Number:	2011-002750-31
Sponsor's Protocol Code Number:	LAL-CL02
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-02-25
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2011-002750-31

A.3

Full title of the trial

A multicenter, randomized, placebo-controlled study of SBC-102 in patients with lysosomal acid lipase deficiency

Studio multicentrico, randomizzato, controllato
con placebo, di SBC-102 in pazienti con carenza di lipasi acida lisosomiale

A.3.1

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

A study of SBC-102 (enzyme replacement therapy) in patients with lysosomal acid lipase deficiency

Studio di SBC-102 (terapia di sostituzione enzimatica) in
pazienti con carenza di lipasi acida lisosomiale

A.3.2

Name or abbreviated title of the trial where available

ARISE (Acid Lipase Replacement Investigating Safety and Efficacy)

A.4.1

Sponsor's protocol code number

LAL-CL02

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	Synageva BioPharma 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	Synageva BioPharma Corp.
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	Synageva Biopharma Corporation
B.5.2	Functional name of contact point	Suki Malhi, Clinical Operations
B.5.3	Address:
B.5.3.1	Street Address	The Cart Shed, The Old Brewery, Priory Lane
B.5.3.2	Town/ city	Burford, Oxfordshire
B.5.3.3	Post code	OX18 4SG
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+44151348 4210
B.5.5	Fax number	+44151348 4214
B.5.6	E-mail	suki.malhi@synageva.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/3/10/827
D.3 Description of the IMP
D.3.1	Product name	sebelipase alfa
D.3.2	Product code	SBC-102
D.3.4	Pharmaceutical form	Solution for 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.3.8	INN - Proposed INN	NA
D.3.9.1	CAS number	1276027-63-4
D.3.9.2	Current sponsor code	SBC-102
D.3.9.3	Other descriptive name	lysosomal acid lipase, Esterase, cholesterol (human gene LIPA), Lysosomal acid lipase (human gene LIPA); USAN: sebelipase alpha
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	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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	Solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Lysosomal Acid Lipase Deficiency

Carenza di lipasi acida lisosomiale

E.1.1.1

Medical condition in easily understood language

Insufficient lysosomal acid lipase activity leading to accumulation of fats in the human body.

Insufficiente attivita lipasi acida lisosomiale conseguente all'accumulo di grassi nel corpo umano

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	14.1
E.1.2	Level	HLT
E.1.2	Classification code	10024579
E.1.2	Term	Lysosomal storage disorders
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

To demonstrate efficacy of SBC-102, relative to placebo, based on normalisation of ALT in patients with LALD.

obiettivo primario è dimostrare l'efficacia di SBC-102 rispetto
al placebo nella normalizzazione dei valori di ALT nei pazienti con LALD

E.2.2

Secondary objectives of the trial

(1) to demonstrate the efficacy of SBC-102, relative to placebo, based on the following parameters: decrease in LDL-c, decrease in non-high density lipoprotein cholesterol (HDL-c), normalization of aspartate aminotransferase (AST), decrease in triglycerides, increase in HDL-c, and, in the subset of subjects for whom the assessments are performed, decrease in liver fat content, improvement in hepatic histology, and decrease in liver volume;
(2) to evaluate the safety, tolerability, and immunogenicity of SBC-102 therapy; and
(3) to further characterise the PK of SBC-102.

1) dimostrare l'efficacia di SBC-102 rispetto al placebo, in base ai seguenti parametri: riduzione dei livelli di LDL-c, riduzione del colesterolo delle lipoproteine a bassa densità (HDL-c), normalizzazione dei livelli di aspartato aminotransferasi (AST),
riduzione dei trigliceridi, aumento dei livelli di HDL-c e, nel sottogruppo di soggetti per i quali sono effettuate le valutazioni, riduzione del contenuto di grasso epatico, miglioramento
dell'istologia epatica e riduzione del volume epatico; (2) valutare la sicurezza, tollerabilità e immunogenicità della terapia SBC-102; e (3) caratterizzare ulteriormente la PK di SBC-102

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Subject and/or subject’s parent or legal guardian understand the full nature and purpose of the study, including possible risks and side effects, and is willing and able to comply with all compulsory study procedures (including liver biopsy and magnetic resonance imaging [MRI] assessments, as applicable) and provides informed consent/permission prior to any study procedures being performed. If the subject is <18 years of age, he/she is willing to provide assent where required per local regulations and if deemed able to do so.
2. Subject is ≥4 years of age on the date of informed consent.
3. Deficiency of lysosomal acid lipase (LAL) enzyme activity confirmed by dried blood spot (DBS) testing at screening, based on the definition of deficiency provided by the central laboratory performing the assay.
4. ALT ≥1.5x ULN (based on the age- and gender-specific normal ranges of the central laboratory performing the assay) on 2 consecutive screening ALT measurements obtained at least 1 week apart.
5. Female subjects of childbearing potential must (a) have negative serum pregnancy test at screening (b) cannot be breastfeeding, and (c) must agree to use a medically acceptable method of preventing conception from the screening visit until 4 weeks after the last dose of study drug administered under this protocol. A female of childbearing potential is defined as a menarchal female who has not had a hysterectomy, bilateral oophorectomy, or medically documented ovarian failure, and who is not postmenopausal.
6. Subjects receiving lipid-lowering therapies must be on a stable dose of the medication for at least 6 weeks prior to randomization and be willing to remain on a stable dose for at least the first 32 weeks of treatment in the study.
7. Subjects receiving medications for the treatment of non-alcoholic fatty liver disease (e.g., glitazones, high-dose vitamin E, metformin, ursodeoxycholic acid [UDCA]) must be on a stable dose for at least 16 weeks prior to randomization and be willing to remain on a stable dose for at least the first 32 weeks of treatment in the study.

Il soggetto e/o i genitori o il tutore legale del soggetto devono comprendere interamente la natura e lo scopo dello studio, inclusi i possibili rischi ed effetti collaterali; il soggetto deve
accettare ed essere in grado di adempiere a tutte le procedure obbligatorie dello studio (incluse la biopsia epatica e la risonanza magnetica per immagini [RMI] se del caso) e deve dare il proprio consenso informato/permesso prima che venga effettuata qualsiasi procedura dello studio. Qualora il soggetto fosse di età <18 anni, deve fornire il proprio consenso ove
richiesto dalla normativa locale e se ritenuto in grado di farlo. 2.L'età dei soggetti deve essere 4 anni alla data del consenso informato. 3. Il deficit dell' attività enzimatica della lipasi acida lisosomiale (LAL) deve essere confermato dall' esame delle macchie di sangue essiccato (Dried Blood Spot, DSB) eseguito durante lo screening, in base alla definizione di deficit fornita dal laboratorio centrale che effettua la prova. 4. Valori di ALT 1,5x ULN (in base all'intervallo dei valori normali specifici per età e sesso stabilito dal laboratorio centrale che effettua la prova) in occasione di 2 misurazioni consecutive dei valori di ALT
allo screening ottenute a distanza di almeno 1 settimana. 5. Le donne in età fertile devono (a) avere un test di gravidanza sul siero negativo allo screening, (b) non possono essere in
allattamento e (c) devono acconsentire a usare un metodo clinicamente accettabile per la prevenzione della gravidanza a partire dalla visita di screening fino a 4 settimane dopo
l'ultima dose del farmaco in studio somministrata in conformità con il protocollo. Una donna in età fertile è definita come una donna in menarca non sottoposta ad isterectomia,
ovariectomia bilaterale o non affetta da insufficienza ovarica clinicamente documentata e non in postmenopausa. 6. I soggetti trattati con farmaci ipolipemizzanti devono assumere un
dosaggio stabile da almeno 6 settimane prima della randomizzazione e devono accettare di assumere tale dosaggio stabile come minimo per le prime 32 settimane del trattamento in
studio. 7. I soggetti in terapia per steatosi epatica di origine non alcolica (ad esempio con glitazoni, vitamina E a dosaggi elevati, metformina, acido ursodesossicolico [Ursodeoxycholic Acid, UDCA]) devono assumere un dosaggio stabile da almeno 16
settimane prima della randomizzazione e devono accettare di assumere tale dosaggio stabile come minimo per le prime 32 settimane del trattamento in studio.

E.4

Principal exclusion criteria

1. Severe hepatic dysfunction (Child-Pugh Class C).
2. Other medical conditions or comorbidities which, in the opinion of the Investigator, would interfere with study compliance or data interpretation, including but not restricted to severe intercurrent illness, known causes of active liver disease other than LALD (e.g., chronic viral hepatitis, autoimmune hepatitis, alcoholic liver disease, or physician concerns about excess alcohol consumption), human immunodeficiency virus (HIV), poorly-controlled diabetes, or cancers other than non-melanoma skin cancer.
3. Previous hematopoietic or liver transplant procedure.
4. Received treatment with high-dose corticosteroids (acute or chronic) within 26 weeks prior to randomization. (Note: Subjects receiving maintenance therapy with low-dose oral, intranasal, topical, or inhaled corticosteroids are considered eligible for the study.)
5. Participated in a study employing an investigational medicinal product within 30 days prior to randomization.
6. Known hypersensitivity to eggs.

1.Grave disfunzione epatica (classe C di Child-Pugh). 2.Altre condizioni cliniche o malattie concomitanti che, secondo il parere dello Sperimentatore, potrebbero interferire con la
compliance dello studio o con l’interpretazione dei dati, tra cui la presenza di una grave malattia concomitante, cause note di malattia epatica attiva diversa da LALD (ad esempio,
epatite virale cronica, epatite autoimmune, malattia epatica di origine alcolica o la preoccupazione da parte del medico di un eccessivo consumo di alcolici), virus dell'immunodeficienza umana (HIV), diabete scarsamente controllato o tipi di cancro
diversi dal tumore cutaneo non melanoma. 3.Precedenti procedure di ematopoeisi o trapianto epatico. 4.Trattamento (acuto o cronico) con alte dosi di corticosteroidi entro 26
settimane prima della randomizzazione (Nota: i soggetti sottoposti a terapia di mantenimento con corticosteroidi a basso dosaggio per via orale, intranasale, topica o inalatoria sono
considerati idonei allo studio). 5.Partecipazione a uno studio su un prodotto medicinale sperimentale entro 30 giorni prima della randomizzazione. 6.Nota ipersensibilità alle uova.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy outcome measure is the proportion of subjects who achieve ALT normalisation (i.e., ALT below the age-and gender-specific ULN provided by the central laboratory performing the assay) at the end of the double-blind treatment period (Week 20).

La misura dell’esito primario di efficacia è la percentuale di pazienti che raggiungono una normalizzazione dei valori di ALT (ossia, valori di ALT inferiori all’ULN, specifici per età e
sesso, forniti dal laboratorio centrale che effettua la prova) al termine del periodo di trattamento in doppio cieco (Settimana 20).

E.5.1.1

Timepoint(s) of evaluation of this end point

At the end of the double-blind treatment period (Week 20)

Alla fine del periodo di trattamento in doppio cieco (20 settimane)

E.5.2

Secondary end point(s)

The secondary efficacy outcome measures include the following changes (or normalisation or improvement rates, as applicable) from baseline to the end of the double-blind treatment period:
(1) Relative reduction in LDL-c
(2) Relative reduction in non-HDL-c
(3) The proportion of subjects with an abnormal baseline AST (i.e., > ULN) who achieve AST normalisation, based on age- and gender-specific normal ranges provided by the central laboratory performing this assay
(4) Relative reduction in triglycerides
(5) Relative increase in HDL-c
And, in the subset of subjects for whom the assessments are performed:
(6) Relative reduction in liver fat content
(7) The proportion of subjects who show improvement in liver histopathology, and
(8) Relative reduction in liver volume.

Le misure dell’esito secondario di efficacia comprendono i seguenti cambiamenti (o percentuali di normalizzazione o miglioramento, a seconda dei casi) dal valore basale alla
fine del periodo di trattamento in doppio cieco: (1) riduzione relativa dei valori di LDL-c; (2) riduzione relativa dei valori di non-HDL-c; (3) la percentuale di soggetti con valori alterati
di AST al valore basale (ossia > ULN) che raggiungono la normalizzazione dei valori di AST, in base all’intervallo dei valori normali specifici per età e sesso fornito dal laboratorio
centrale che effettua questa prova; (4) riduzione relativa dei livelli dei trigliceridi; (5) aumento relativo dei valori di HDL-c; e, nel sottogruppo dei soggetti su cui vengono eseguite
le valutazioni, (6) riduzione relativa del contenuto del grasso epatico; (7) percentuale di soggetti con miglioramento dell’istopatologia epatica; e (8) riduzione relativa del volume
epatico.

E.5.2.1

Timepoint(s) of evaluation of this end point

The following are all assessed at the end of the double-blind treatment period:
(1) LDL-c
(2) Non-HDL-c
(3) AST normalisation
(4) Triglycerides
(5) HDL-c
(6) Right lobe liver fat content
(7) Liver histopathology
(8) Liver volume

Alla fine del trattamento in doppio cieco sono valutati i seguenti: (1) LDL-c (2) Non-HDL-c (3) normalizzazione AST (4) Trigliceridi (5) HDL-c (6) lobo epatico destro per il contenuto di grasso (7) Istopatologia del fegato (8) Volume del fegato

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

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

Yes

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

20 settimene in doppio cieco e successive 130 settimene in aperto

20 week double-blind treatment period and then up to another 130 weeks open-label treatment period

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

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

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

Argentina

Australia

Belgium

Brazil

Chile

Croatia

Cyprus

Czech Republic

Denmark

France

Germany

Greece

Israel

Italy

Mexico

Netherlands

Poland

Romania

Russian Federation

South Africa

Spain

Sweden

Taiwan

Turkey

Ukraine

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

The LVLS will be a follow-up call at least 4 weeks after the last dose of study drug

LVLS corrispondente alla telefonota di Follow-up 4 settimane dopo l'ultima dose di farmaco in studio.

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.1.3.1

Number of subjects for this age range:

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Minor subjects from 4 to 17 years old. They will be provided with an assent form to request their assent to participate.

Minori dai 4 ai 17 anni.Sarà fornito loro il modulo di Assenso per
richiedere il loro consenso a partecipare

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)

There is no approved treatment for the condition. The subjects will continue having their disease managed as agreed with their treating physicians or may be eligible for compassionate use or expanded access to the IMP.

Non vi sono trattamenti approvati per la condizione clinica. I soggetti saranno seguiti a discrezione dei propri medici curanti e potranno beneficiare del trattamento in studio ad uso compassionevole o ad expanded access.

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

2013-04-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-04-15

P. End of Trial
P.	End of Trial Status	Completed

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