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    Summary
    EudraCT Number:2011-004287-30
    Sponsor's Protocol Code Number:LAL-CL06
    National Competent Authority:Croatia - MIZ
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-09-03
    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
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedCroatia - MIZ
    A.2EudraCT number2011-004287-30
    A.3Full title of the trial
    A Multicenter, Open-Label Study of Sebelipase Alfa in Patients with Lysosomal Acid Lipase Deficiency
    OTVORENO MULTICENTRIČNO ISPITIVANJE SEBELIPAZE ALFA U ISPITANIKA S POMANJKANJEM LIZOSOMSKE KISELE LIPAZE
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of sebelipase alfa in a broad population of patients with Lysosomal Acid Lipase Deficiency (LALD).
    ISPITIVANJE SEBELIPAZE ALFA U ŠIROJ POPULACIJI ISPITANIKA S POMANJKANJEM LIZOSOMSKE KISELE LIPAZE
    A.4.1Sponsor's protocol code numberLAL-CL06
    A.5.3WHO Universal Trial Reference Number (UTRN)U1111-1152-7171
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/112/2013
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAlexion Pharmaceuitcals Inc
    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 supportAlexion Pharmaceuticals Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAlexion Pharmaceuticals Inc
    B.5.2Functional name of contact pointHarold Pestana, Assoc Dir Clin Ops
    B.5.3 Address:
    B.5.3.1Street Address33 Hayden Avenue
    B.5.3.2Town/ cityLexington, MA
    B.5.3.3Post code02421
    B.5.3.4CountryUnited States
    B.5.4Telephone number001 7813579900
    B.5.5Fax number001 7813579901
    B.5.6E-mailPestanaH@alxn.com
    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 Concentrate for solution for injection/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 INNsebelipase alfa
    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.3.9.4EV Substance CodeSUB121647
    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.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee 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
    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 (LALD)
    POMANJKANJE LIZOSOMSKE KISELE LIPAZE
    E.1.1.1Medical condition in easily understood language
    Insufficient lysosomal acid lipase activity leading to accumulation of fats in the human body.
    POMANJKANJE LIZOSOMSKE KISELE LIPAZE KOJE DOVODI DO AKUMULACIJE MASNOĆA U TIJELU
    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 19.0
    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
    The primary objective of this study is to evaluate the safety of sebelipase alfa in a broad population of patients with LALD than previously studied.
    Primarni cilj ovog ispitivanje je procjena sigurnosti sebelipaze alfa u široj populaciji ispitanika s pomanjkanjem lizosomske kisele lipaze nego što je ranije ispitivana.
    E.2.2Secondary objectives of the trial
    The secondary objectives of this study are (1) to evaluate effects of sebelipase alfa relative to Baseline assessment of lipid metabolism and liver function (including histopathology); (2) to evaluate the effects of sebelipase alfa on additional clinical parameters of LALD including those not previously well characterized in the literature, and (3) to evaluate the effects of sebelipase alfa on growth parameters in pediatric patients presenting with evidence of growth delay.
    Sekundarni ciljevi ovog ispitivanja su (1) procjena učinaka sebelipaze alfa u odnosu na testove metabolizma masnoća i funkcije jetre (uključujući histopatologiju) na početku liječenja; (2) procjena učinaka sebelipaze alfa na dodatne kliničke parametre pomanjkanja lizosomske kisele lipaze, uključujući i one koji nisu prethodno okarakterizirani u literaturi i (3) procjena učinaka sebelipaze alfa na parametre rasta u ispitanika pedijatrijske dobi koji se prezentiraju s dokazom usporenog rasta.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Subject will be > 8 months of age at the time of dosing.
    2.Subject or subject’s parent or legal guardian (if applicable) consents to participation in the study. If the subject is of minor age, he/she is willing to provide assent where required per local regulations, and if deemed able to do so.
    3.Confirmation of LAL Deficiency diagnosis as determined by the central lab; a subject who received a liver or hematopoietic stem cell transplant who does not show evidence of LAL enzyme deficiency by DBS due to the effects of transplantation must have either:
    a.Molecular genetic testing which confirms mutations in both alleles of the LIPA gene; OR
    b.Appropriately documented (based on consultation with the Sponsor) historical result of an enzyme test prior to hematopoietic or liver transplantation
    4. Subjects > 8 months but < 4 years of age at Screening will have at least 1 of the following documented clinical manifestations of LAL Deficiency:
    a.Dyslipidemia (defined as Screening low-density lipoprotein cholesterol (LDL-C) > 130 mg/dL; triglycerides (TG) > 200 mg/dL);
    b.Elevated transaminases (ALT ≥1.5x ULN);
    c.Impaired growth as defined as:
    i.WFA or SFA less than the age- and gender- appropriate 5th percentile on a standard World Health Organization (WHO) (subjects ≤ 24 months of age) or Centers for Disease Control and Prevention (CDC) (subjects > 24 months and < 4 years of age) WFA or SFA chart for at least 3 months prior to study entry; OR
    ii.Poor weight gain as evidenced by calculated weight percentile decreasing across 2 major percentile (99th, 97th, 95th, 90th, 75th, 50th, 25th, 10th, 5th, 3rd, and 1st) lines on a standard WHO (subjects ≤24 months of age) or CDC (subjects > 24 months and <4 years of age) WFA chart over a period of 6 months prior to study entry;
    d.Suspected malabsorption with:
    i.Persistent unexplained gastrointestinal symptoms such as nausea, diarrhea, abdominal pain, and bloating; OR
    ii.Unexplained anemia, or other abnormalities suggestive of malabsorption; AND
    iii.Documented small intestinal disease involvement on a small bowel biopsy performed within 1 year of Screening
    e.Other clinical manifestation of LAL Deficiency in the opinion of the investigator and in consultation with the Sponsor.
    5.Subjects ≥ 4 years of age at Screening will have at least 1 of the following documented clinical manifestations of LAL Deficiency:
    a. Evidence of advanced liver disease at Screening accompanied by:
    i.Clinically significant portal hypertension as defined by a hepatic venous pressure gradient (HVPG) greater than or equal to 10 mmHg; OR
    ii.Documented esophageal varices at Screening
    b.Disease recurrence in subjects with past liver or hematopoietic transplants
    c.Persistent dyslipidemia (defined as LDL-C > 130mg/dL, TG > 200mg/dL, or high-density lipoprotein cholesterol (HDL C) <40mg/dL in males, and < 50mg/dL in females) that has persisted despite 3 or more months of treatment with one or more lipid-lowering therapies such as statins, cholesterol absorption inhibitors (ezetimibe), combination therapies (single-pill; ezetimibe/simvastatin, niacin/simvastatin), fibrates (fenofibrate, gemfibrozil, fenofibric acid), niacin or bile acid sequestrants (cholestyramine, colestipol, colesevelam);
    d.Suspected malabsorption based on the following manifestations:
    i.Documented small intestinal involvement by small bowel biopsy performed within 1 year of Screening; AND
    ii.Unexplained iron deficiency, osteopenia, weight loss or chronic diarrhea; OR
    iii.Impaired growth in pediatric subjects defined as:
    1.WFA or SFA less than the age- and gender- appropriate 5th percentile on a standard CDC WFA chart for at least 6 months prior to study entry; OR
    2.Poor weight gain as evidenced by calculated weight percentile decreasing across 2 major percentile (99th, 97th, 95th, 90th, 75th, 50th, 25th, 10th, 5th, 3rd, and 1st) lines on a standard CDC WFA chart over a period of 6 months prior to study entry;
    e.Other clinical manifestation of LAL Deficiency in the opinion of the investigator and in consultation with the Sponsor.
    6.Male and female subjects of childbearing potential must agree to use a highly reliable method of birth control (expected failure rate less than 5% per year) from the screening visit through 4 weeks after the last dose of study drug.
    7.Women of childbearing potential must have a negative serum pregnancy test prior to entering the study.
    8.Subjects receiving lipid-lowering therapies must be on a stable dose of the medication or stable apheresis regimen for at least 4 weeks prior to treatment and be willing to remain on a stable dose for at least the first 12 weeks of treatment in the study.
    9.Subjects receiving medications for the treatment of nonalcoholic fatty liver disease must be on a stable dose for at least 4 weeks prior to treatment and be willing to remain on a stable dose for at least the first 12 weeks of treatment in the study.
    1.Ispitanik je star >8 mj u trenutku davanja prve doze
    2.Ispitanik/ispitanikov roditelj/zakonski zastupnik pristaje na sudjelovanje u ispitivanju. Ako je ispitanik maloljetan te ako se smatra da je sposoban to učiniti, mora biti voljan dati pristanak tamo gdje to zahtijevaju lokalni propisi
    3.Potvrda dijagnoze pomanjkanja lizosomske kisele lipaze prema nalazima sred laboratorija. Ispitanik koji je primio transplantaciju jetre ili hematopoetskih matičnih stanica i koji zbog učinaka transplantacije ne pokazuje dokaze pomanjkanja enzima lizosomske kisele lipaze na testu aktivnosti enzima metodom suhe kapi krvi mora imati:
    a.molekularni genetski test koji potvrđuje mutacije u oba alela gena lipaze A ili
    b.prikladno dokumentiran povijesni rezultat enzimskog testa koji je prethodio transplantaciji jetre ili hematopoetskih matičnih stanica
    4.Ispitanici stari >8 mj, ali <4 god u trenutku probira imaju najmanje 1 od sljedećih dokumentiranih klin. manifestacija pomanjkanja lizosomske kisele lipaze:
    a.dislipidemija
    b.povišene vrijednosti transaminaza
    c.usporeni rast definiran kao
    i.težina i stas u odnosu na dob <5. percentila odgovarajućeg dobu i spolu prema standardnim kartama za težinu ili stas SZO (ispitanici starosti ≤ 24 mj) ili CDC SAD-a (ispitanici starosti ≥ 24 mj i <4 god) tijekom najmanje 3 mj prije uključivanja u ispitivanje ili
    ii.spor porast težine kao što pokazuje izračunati percentil težine koji se smanjuje preko 2 veće crte percentila (99., 97., 95., 90., 75., 50., 25., 10., 5., 3. i 1.) na standardnim kartama za težinu SZO (ispitanici starosti ≤ 24 mj) ili CDC SAD-a (ispitanici starosti ≥ 24 mj i < 4 god) tijekom razdoblja od 6 mj prije uključivanja u ispitivanje
    d.sumnja na malapsorpciju s
    i.perzistentnim nerazjašnjenim gastrointestinalnim simptomima: mučnina, proljev, bolovi u trbuhu i nadimanje ili
    ii.nerazjašnjena anemija ili druge abnormalnosti koje ukazuju na malapsorpciju i
    iii.uključenje bolesti tankog crijeva dokumentirano biopsijom tankog crijeva napravljenom u razdoblju od 1 god prije probira
    e.ostale klin. manifestacije pomanjkanja lizosomske kisele lipaze prema mišljenju ispitivača i u suglasju s naručiteljem
    5.Ispitanici stari ≥4 god u trenutku probira imaju najmanje 1 od sljedećih dokumentiranih manifestacija pomanjkanja lizosomske kisele lipaze
    a.dokaz uznapredovale bolesti jetre u trenutku probira popraćen s
    i.klinički značajnom portalnom hipertenzijom definiranom gradijentom tlaka u jetrenoj veni ≥ 10 mmHg ili
    ii.dokumentiranim varikozitetom jednjaka na probiru
    b.povratak bolesti u ispitanika koji su primili transplantaciju jetre ili hematopoetskih matičnih stanica
    c.perzistentna dislipidemija (definirana kao kolesterol lipoproteina niske gustoće (LDL-C) na probiru > 130 mg/dl i trigliceridi > 200 mg/dl ili kolesterol lipoproteina visoke gustoće (HDL-C) < 40 mg/dl u muškaraca i < 50 mg/dl u žena) koji opstaje unatoč 3 ili više mj liječenja s jednim ili više lijekova za smanjenje razine lipida poput statina, inhibitora apsorpcije kolesterola (ezetimib), kombiniranih terapija (jednom kombiniranom tabl ezetimiba/simvastatina, niacina/simvastatina), fibrata (fenofibrat, gemfibrozil, fenofibrična kiselina), niacina ili sekvestranta žučne kiseline (kolestiramin, kolestipol, kolesevelam)
    d.sumnja na malapsorpciju na temelju sljedećih manifestacija
    i.uključenje tankog crijeva dokumentirano biopsijom tankog crijeva u razdoblju od 1 god prije probira i
    ii.nerazjašnjeno pomanjkanje željeza, osteopenija, gubitak tjelesne težine ili kronični proljev ili
    iii.usporen rast u ispitanika pedijatrijske dobi definiran kao
    1.težina i stas u odnosu na dob <5. percentila odgovarajućeg dobu i spolu prema standardnoj karti CDC SAD-a tijekom najmanje 6 mj prije uključivanja u ispitivanje ili
    2.spor porast težine kao što pokazuje izračunati percentil težine koji se smanjuje preko 2 veće crte percentila (99., 97., 95., 90., 75., 50., 25., 10., 5., 3. i 1.) na standardnim kartamaza težinu CDC SAD-a tijekom razdoblja od 6 mj prije uključivanja u ispitivanje
    e.ostale kliničke manifestacije pomanjkanja lizosomske kisele lipaze prema mišljenju ispitivača i u suglasju s naručiteljem
    6.Ispitanice i ispitanici koji su reproduktivno sposobni moraju pristati na korištenje visoko pouzdane metode kontracepcije od posjeta za probir do 4. tj nakon zadnje doze ispitivanog lijeka
    7.Žene koje mogu zatrudnjeti moraju prije uključivanja u ispitivanje imati neg. serumski test na trudnoću
    8.Ispitanici koji primaju terapije za snižavanje masnoća moraju biti na stabilnoj dozi lijekova ili stabilnom režimu afereze tijekom najmanje 4 tj prije liječenja te moraju biti voljni ostati na stabilnoj dozi najmanje prvih 12 tj ispitivanog lijeka
    9.Ispitanici koji primaju lijekove za liječenje nealkoholne masne bolesti jetre moraju biti na stabilnoj dozi najmanje 4 tj prije liječenja te moraju biti voljni ostati na stabilnoj dozi najmanje prvih 12 tj ispitivanog lijeka
    E.4Principal exclusion criteria
    1. Subject meets eligibility criteria for another interventional study of sebelipase alfa in LAL Deficiency that is open for enrollment in the region where the subject will receive treatment.
    2. Subject has known causes of active liver disease other than LAL Deficiency which have not been adequately treated (e.g., chronic viral hepatitis, autoimmune hepatitis, alcoholic liver disease).
    3. Subject is unable or unwilling to comply with study procedures.
    4. Subject received a hematopoietic stem cell or liver transplant < 2 years from the time of dosing.
    5. Females who are nursing or pregnant.
    6. Subject with co-morbidities other than complications due to LAL Deficiency which, in the opinion of the Investigator and in consultation with the Sponsor, are irreversible or associated with a high mortality risk within 6 months, or would interfere with study compliance or data interpretation (e.g. excessive alcohol consumption).
    7. Exposure to any investigational product within 30 days of Screening for a small molecule and 60 days of Screening for a biologic.
    8. Known hypersensitivity to eggs.
    1. Ispitanik ispunjava kriterije podobnosti za drugo intervencijsko ispitivanje sebelipaze alfa za pomanjkanje lizosomske kisele lipaze koje je otvoreno za uključivanje u regiji gdje će ispitanik primati lijek.
    2. Ispitanik pored pomanjkanja lizosomske kisele lipaze ima poznate i druge uzroke aktivne bolesti jetre (na primjer, kronični virusni hepatitis, autoimuni hepatitis, alkoholna bolest jetre) koja nije bila prikladno liječena.
    3. Ispitanik nije sposoban ili voljan uskladiti se s postupcima iz ispitivanja.
    4. Ispitanik je primio transplantaciju hematopoetskih matičnih stanica ili jetre < 2 godine od trenutka davanja lijeka.
    5. Trudnice ili dojilje.
    6. Ispitanik s drugim komorbiditetima koji su, prema mišljenju ispitivača i u suglasju s naručiteljem, nepovratni ili povezani s visokim rizikom smrtnosti u razdoblju od 6 mjeseci ili bi ometali usklađivanje s ispitivanjem ili interpretaciju podataka (na primjer, prekomjerna konzumacija alkohola), osim komplikacija zbog pomanjkanja lizosomske kisele lipaze.
    7. Izloženost bilo kojem ispitivanom proizvodu u razdoblju od 30 dana prije probira za proizvode malih molekula i 60 dana za biološke proizvode.
    8. Poznata preosjetljivost na jaja.
    E.5 End points
    E.5.1Primary end point(s)
    Safety endpoints will include the incidence of adverse events (AEs), SAEs, and infusion-related reactions (IRRs); changes from Baseline in 12-lead electrocardiograms (ECGs) and clinical laboratory tests (hematology, serum chemistry [including lipid panel], and urinalysis); changes in vital signs during and after infusion, relative to pre-infusion values; physical examination findings; use of concomitant medications/therapies; characterization of antidrug antibodies (ADAs) including seroconversion rate, time to seroconversion, ADA titer by time point, peak ADA titer, time to peak ADA titer, and tolerization. The effect of ADAs on the safety of sebelipase alfa will also be explored, in particular, the relationship between ADA-positive patients and the incidence of IRRs. Functional and overall development in patients ≤ 6 years of age will be assessed, as determined by Denver II scores.
    Sigurnosne krajnje točke uključivat će učestalost štetnih događaja, ozbiljnih štetnih događaja i reakcija povezanih s infuzijom; promjene od početka liječenja na 12-kanalnim elektrokardiogramima i kliničkim laboratorijskim testovima (hematologija, serumska kemija [uključujući pretrage lipida] i analiza mokraće); promjene vitalnih znakova tijekom i nakon infuzije u odnosu na vrijednosti prije infuzije; nalaze fizikalnog pregleda; korištenje popratnih lijekova/terapija; karakterizaciju protutijela protiv lijeka, uključujući stopu serokonverzije, vrijeme do serokonverzije, titre protutijela protiv lijeka prema vremenskim točkama, najviši titar protutijela protiv lijeka, vrijeme do najvišeg titra protutijela protiv lijeka i stvaranje tolerancije. Također će se istraživati učinak protutijela protiv lijeka na sigurnost sebelipaze alfa, a posebice odnos između ispitanika pozitivnih na protutijela protiv lijeka i učestalosti reakcija povezanih s infuzijom. Procijenit će se funkcionalni i ukupni razvoj u ispitanika starosti ≤ 6 godina na način utvrđen prema rezultatima upitnika Denver II.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Screening will occur within 45 days. Eligible patients will receive intravenous infusions of sebelipase alfa for up to 96 weeks, an expanded treatment period of a maximum of up to 48 weeks. All patients will receive a starting dose of 1 mg·kg-1 qow. Dose increases (up to 3 mg·kg-1 qw) will be permitted during the treatment period. The followup period will be 4 weeks from the last infusion of sebelipase alfa.
    Probir će se napraviti u 45 dana. Podobni ispitanici će primati sebelipazu alfa infuziju intravenozno do 96 tjedana, produžetak razdoblja liječenja od najviše 48 tjedana. Svi će ispitanici primiti početnu dozu od 1 mg•kg-1 svaki drugi tjedan. Povećanje doze (do 3 mg•kg 1 tjedno) bit će dopušteno za vrijeme trajanja liječenja. Razdoblje praćenja trajat će 4 tjedna nakon zadnje infuzije sebelipaze alfa.
    E.5.2Secondary end point(s)
    Secondary outcome measures include the following changes or percent change from Baseline to the end of the treatment period: (1) decrease in Alanine Aminotransferase (ALT); (2) decrease in Aspartate Aminotransferase (AST); (3) decrease in LDL-C; (4) decrease in non-HDL-C; (5) increase in HDL-C; (6) decrease in TG, (7) decrease in Child-Pugh status, (8) decrease in United Kingdom Model for End-Stage Liver Disease (UK-ELD) score. In the subset of subjects for whom these assessments are performed: (9) improvement in hepatic histology; (10) decrease in liver and spleen volume by magnetic resonance imaging (MRI); and (11) decrease in liver fat fraction by MRI. The effect of sebelipase alfa on growth parameters in pediatric subjects with manifestations of impaired growth will be measured.
    Additional clinical, biochemical and hematological abnormalities will also be evaluated, including (1) total and conjugated bilirubin, (2) gamma glutamyltransferase (GGT), (3) markers of macrophage activation, (4) high sensitivity C-reactive protein, (4) hemoglobin level, and (5) platelet count.
    Exploratory measures of additional clinical manifestations of LAL Deficiency not previously well characterized in the literature will include changes in functional assessments outcomes.
    Pharmacokinetics
    PK parameters (in subjects for whom these assessments are performed) will be reported, as the data permit, and may include serum clearance and apparent volume of distribution estimates along with secondary parameters of area under the concentration-time curve, maximum observed concentration, time to maximum observed concentration, and terminal elimination half-life (t1/2). The effect of ADAs on sebelipase alfa PK will also be explored. PK analysis will be discussed in the statistical analysis plan (SAP).
    Health-Related Quality of Life
    Exploratory HRQOL measures will include changes from Baseline in scores for the Functional Assessment of Chronic Illness Therapy-Fatigue scale, Chronic Liver Disease Questionnaire, or Pediatric Quality of Life Inventory (PedsQL™) Generic Core Scales, as appropriate to the age of the subject.
    Pharmacodynamics
    Exploratory disease-related biomarkers, which may be identified based on emerging information from the sebelipase alfa development program and scientific literature, will be analyzed by changes or percent changes over time.
    Sekundarne mjere ishoda uključuju sljedeće promjene ili postotne promjene od početka liječenja do kraja razdoblja liječenja: (1) smanjenje alanin aminotransferaze (ALT); (2) smanjenje aspartat aminotransferaze (AST); (3) smanjenje kolesterola lipoproteina niske gustoće; (4) smanjenje ukupnog kolesterola ne računajući kolesterola visoke gustoće (non-HDL-C); (5) povećanje kolesterola lipoproteina visoke gustoće; (6) smanjenje triglicerida; (7) smanjenje Child-Pugh- statusa; (8) smanjenje rezultata prema britanskom modelu za krajnju fazu bolesti jetre (UK-ELD). U podskupini ispitanika za koje se rade ti testovi: (9) poboljšanje histologije jetre; (10) smanjenje veličine jetre i slezene utvrđeno snimkama magnetske rezonance i (11) smanjenje lipidnih frakcija jetre utvrđeno snimkama magnetske rezonance. Izmjerit će se učinak sebelipaze alfa na parametre rasta u ispitanika pedijatrijske dobi s manifestacijama usporenog rasta.
    Procijenit će se i dodatne kliničke, biokemijske i hematološke abnormalnosti uključujući (1) ukupni i konjugirani bilirubin, (2) gama-glutamiltransferazu (GGT), (3) markere aktivacije makrofaga (4) visoko osjetljivi C-reaktivni protein, (4) razinu hemoglobina i (5) broj trombocita.
    Istraživačka mjerenja dodatnih kliničkih manifestacija pomanjkanja lizosomske kisele lipaze koje prethodno nisu dobro okarakterizirane u literaturi uključivat će promjene u ishodima funkcionalnih testova.
    Farmakokinetika
    O farmakokinetičkim parametrima (u ispitanika za koje se ti testovi provode) izvijestit će se u mjeri u kojoj to podaci omogućavaju, a mogu uključivati procjene serumskog klirensa i prividnog volumena distribucije uz sekundarne parametre površine ispod krivulje koncentracija-vrijeme, maksimalne opažene koncentracije, vrijeme do maksimalne opažene koncentracije i terminalno poluvrijeme eliminacije. Također će se istražiti učinak protutijela protiv lijeka na farmakokinetiku sebelipaze alfa. Farmakokinetička analiza će se razmatrati u planu statističke analize.
    Kvaliteta života povezana sa zdravljem
    Istraživačke mjere kvalitete života povezane sa zdravljem uključuju promjene od početka liječenja u rezultatima funkcionalne procjene terapije za kroničnu bolesti – ljestvice umora upitnika o kroničnoj bolesti jetre ili glavne opće mjere pedijatrijskog upitnika o kvaliteti života (PedsQL™) , prilagođeno starosti ispitanika.
    Farmakodinamika
    Istraživački biomarkeri povezani s bolešću koji se mogu identificirati na temelju informacija koje proizlaze iz programa za razvoj sebelipaze alfa i znanstvene literature analizirat će se prema promjenama ili postotnim promjenama tijekom vremena.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Screening will occur within 45 days.Eligible patients will receive intravenous infusions of sebelipase alfa for up to 96 weeks. All patients will receive a starting dose of 1 mg·kg-1 qow. Dose increases (up to 3 mg·kg-1 qw) will be permitted during the treatment period. The follow-up period will be 4 weeks from the last infusion of sebelipase alfa.
    Probir će se napraviti u 45 dana. Podobni ispitanici će primati sebelipazu alfa infuziju intravenozno do 96 tjedana. Svi će ispitanici primiti početnu dozu od 1 mg•kg-1 svaki drugi tjedan. Povećanje doze (do 3 mg•kg 1 tjedno) bit će dopušteno za vrijeme trajanja liječenja. Razdoblje praćenja trajat će 4 tjedna nakon zadnje infuzije sebelipaze alfa.
    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 Yes
    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.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    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 No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA10
    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
    Australia
    Belgium
    Brazil
    Canada
    Croatia
    Denmark
    Germany
    Italy
    Japan
    Mexico
    Russian Federation
    Spain
    Turkey
    United Kingdom
    United States
    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
    Zadnji posjet zadnjeg ispitanika će biti 4 tjedna nakon zadnje doze sebelipaze alfa.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months11
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months11
    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: 12
    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) Yes
    F.1.1.4.1Number of subjects for this age range: 1
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 6
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 5
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 7
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 1
    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.3.3.6.1Details of subjects incapable of giving consent
    Eligible patients starting at 8 months of age will be enrolled into the study. Patient’s parent or legal guardian consents to participation in the study, if the patient is of minor age and deemed unable to do so.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state1
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 10
    F.4.2.2In the whole clinical trial 20
    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.
    Nema odobrenog lijeka za ovu bolest. Ispitanici će nastaviti primati terapiju dogovorenu sa svojim liječnikom ili mogu biti podobni za milosrdno davanje ispitivanog lijeka ili izravan pristup lijeku.
    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 Decision2014-07-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-06-12
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-12-28
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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