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    Summary
    EudraCT Number:2011-004287-30
    Sponsor's Protocol Code Number:LAL-CL06
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2014-04-18
    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 ConcernedItaly - Italian Medicines Agency
    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
    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).
    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 SponsorSynageva BioPharma Corp.
    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 Corp.
    B.5.2Functional name of contact pointSynageva Clinical Operations
    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 number17813579900
    B.5.5Fax number17813579901
    B.5.6E-mailClinicalTrials@Synageva.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)
    E.1.1.1Medical condition in easily understood language
    Insufficient lysosomal acid lipase activity leading to accumulation of fats in the human body.
    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 16.1
    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
    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.
    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.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patient will be > 8 months of age at the time of dosing.
    2. Confirmation of LALD diagnosis as determined by the central lab; a patient 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 (performed in dry blood spots, leukocytes or fibroblasts).
    3. Patients > 8 months but < 4 years of age at Screening will have at least 1 of the following documented clinical manifestations of LALD:
    a. Dyslipidemia (defined as Screening LDL-C > 130 mg/dL; TG
    > 200 mg/dL);
    b. Elevated transaminases (ALT ≥1.5x ULN (based on the ageand
    gender-specific normal ranges of the central laboratory performing the assay);
    c. Impaired growth as defined as:
    i. WFA or SFA less than the age- and gender appropriate 5th percentile on a standard WHO or CDC 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 lines on a standard WHO (patients < 24 months of age) or CDC (patients ≥ 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 (e.g., osteomalacia, hypoalbuminaemia, prolonged bleeding time due to vitamin K deficiency); AND
    iii. Documented small intestinal disease involvement on
    a small bowel biopsy performed within 1 year of Screening
    e. Other clinical manifestation of LALD in the opinion of the
    investigator and in consultation with the Sponsor (e.g.,
    abnormal cardiac or pulmonary functions, or presence of
    lymphadenopathy by imaging or palpation).
    4. Patients ≥ 4 years of age at Screening will have at least 1 of the
    following documented clinical manifestations of LALD:
    a. Evidence of advanced liver disease (e.g., cirrhosis confirmed
    by imaging or biopsy, and Child-Pugh C) 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 (historical or by
    esophagogastroduodenoscopy (EGD) at Screening (unless medically contraindicated due to high risk of endoscopy-related bleeding based on presence of esophageal varices on endoscopy carried out within 3 months of assessment).
    b. Histologically confirmed disease recurrence in patients with
    past liver or hematopoietic transplants (e.g., re-accumulation
    of lipid containing Kupffer cells, recurrence of fibrosis);
    c. Persistent dyslipidemia (defined as LDL-C >130mg/dL, triglycerides >200mg/dL, or 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 patients defined as:
    1. WFA or SFA less than the age- and genderappropriate
    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 lines on a standard CDC
    WFA chart over a period of 6 months prior to
    study entry;
    e. Other clinical manifestation of LALD in the opinion of the
    investigator and in consultation with the Sponsor (e.g.,
    abnormal cardiac or pulmonary functions, or presence of
    lymphadenopathy by imaging or palpation).
    5. Male and female patients of childbearing potential must agree to use birth control
    6. Women of childbearing potential must have a negative serum
    pregnancy test prior to entering the study.
    7. Patients 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 for first 12 weeks of the study.
    8. Patients receiving medications for the treatment of nonalcoholic fatty liver disease must be on a stable dose for at least 4 weeks prior and for first 12 weeks of study.
    E.4Principal exclusion criteria
    A patient who meets any of the following exclusion criteria will be ineligible for this study:
    1. Patient meets eligibility criteria for another interventional study of sebelipase alfa in LALD that is open for enrollment in the region where the patient will receive treatment.
    2. Patient has known causes of active liver disease other than LALD which have not been adequately treated (e.g., chronic viral hepatitis, autoimmune hepatitis, alcoholic liver disease).
    3. Patient is unable or unwilling to comply with study procedures.
    4. Patient received a hematopoietic stem cell or liver transplant <2 years from the time of dosing.
    5. Females who are nursing or pregnant.
    6. Patient with co-morbidities other than complications due to LALD 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.
    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.
    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. 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.
    E.5.2Secondary end point(s)
    Secondary outcome measures for efficacy 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 triglyceride, (7) decrease in Child-Pugh status, (8) decrease in United Kingdom Model for End-Stage Liver Disease (UK-ELD) score. In the subset of patients for whom these assessments are performed: (9) improvement in hepatic histology; (10) decrease in liver and spleen volume by MRI; and (11) decrease in liver fat fraction by MRI. The effect of sebelipase alfa on growth parameters in pediatric patients 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) highsensitivity C-reactive protein, (4) hemoglobin level, and (5) platelet count.
    Exploratory measures of additional clinical manifestations of LALD not previously well characterized in the literature will include changes in functional assessments outcomes.
    Pharmacokinetics PK parameters (in patients 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 patient.
    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.
    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.
    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 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 concerned2
    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
    Brazil
    Canada
    Croatia
    Denmark
    Germany
    Italy
    Japan
    Mexico
    Poland
    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
    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 state5
    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.
    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 Decision2014-07-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-09-18
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2017-04-03
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