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    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
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    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2011-002750-31
    A.3Full 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.3.1Title 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.3.2Name or abbreviated title of the trial where available
    ARISE (Acid Lipase Replacement Investigating Safety and Efficacy)
    ARISE (Acid Lipase Replacement Investigating Safety and Efficacy)
    A.4.1Sponsor's protocol code numberLAL-CL02
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorSynageva BioPharma Corporation
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportSynageva BioPharma Corp.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSynageva Biopharma Corporation
    B.5.2Functional name of contact pointSuki Malhi, Clinical Operations
    B.5.3 Address:
    B.5.3.1Street AddressThe Cart Shed, The Old Brewery, Priory Lane
    B.5.3.2Town/ cityBurford, Oxfordshire
    B.5.3.3Post codeOX18 4SG
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+44151348 4210
    B.5.5Fax number+44151348 4214
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/10/827
    D.3 Description of the IMP
    D.3.1Product namesebelipase alfa
    D.3.2Product code SBC-102
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNA
    D.3.9.1CAS number 1276027-63-4
    D.3.9.2Current sponsor codeSBC-102
    D.3.9.3Other descriptive namelysosomal acid lipase, Esterase, cholesterol (human gene LIPA), Lysosomal acid lipase (human gene LIPA); USAN: sebelipase alpha
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Lysosomal Acid Lipase Deficiency
    Carenza di lipasi acida lisosomiale
    E.1.1.1Medical 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.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level HLT
    E.1.2Classification code 10024579
    E.1.2Term Lysosomal storage disorders
    E.1.2System Organ Class 100000004850
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main 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.2.2Secondary 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.2.3Trial contains a sub-study No
    E.3Principal 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.4Principal 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.5.1Primary 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.5.1.1Timepoint(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.5.2Secondary 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
    E.5.2.1Timepoint(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.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E. trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E. 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.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA23
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Czech Republic
    Russian Federation
    South Africa
    United Kingdom
    E.8.7Trial 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.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 26
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) Yes
    F. of subjects for this age range: 9
    F.1.1.6Adolescents (12-17 years) Yes
    F. of subjects for this age range: 17
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 29
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F. 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.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state3
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 40
    F.4.2.2In the whole clinical trial 55
    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
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-04-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-04-15
    P. End of Trial
    P.End of Trial StatusCompleted
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