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    Summary
    EudraCT Number:2014-002550-39
    Sponsor's Protocol Code Number:PDY13949
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2016-04-25
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2014-002550-39
    A.3Full title of the trial
    4-part, open-label, multicenter, multinational study of the
    safety, tolerability, pharmacokinetics, pharmacodynamic, and exploratory
    efficacy of venglustat in combination with Cerezyme in adult patients with
    Gaucher disease Type 3 with venglustat monotherapy extension
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Venglustat in Combination with Cerezyme in Adult Patients with Gaucher
    Disease Type 3 with venglustat monotherapy extension
    A.3.2Name or abbreviated title of the trial where available
    LEAP
    A.4.1Sponsor's protocol code numberPDY13949
    A.5.3WHO Universal Trial Reference Number (UTRN)U1111-1156-4278
    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 SponsorGenzyme 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 supportGenzyme Corporation
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSanofi-Aventis Deutschland GmbH
    B.5.2Functional name of contact point
    B.5.3.4CountryGermany
    B.5.6E-mailmedinfo.de@sanofi.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 numberEMA/OD/152/14
    D.3 Description of the IMP
    D.3.1Product nameVenglustat
    D.3.2Product code GZ402671
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 1401090-53-6
    D.3.9.2Current sponsor codeSAR402671A / GZ402671
    D.3.9.3Other descriptive nameGenz-682452-AU
    D.3.9.4EV Substance CodeSUB166602
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number15
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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 No
    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.IMP: 2
    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 numberEMA/OD/152/14
    D.3 Description of the IMP
    D.3.1Product nameVenglustat
    D.3.2Product code GZ402671
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 1401090-53-6
    D.3.9.2Current sponsor codeSAR402671A / GZ402671
    D.3.9.3Other descriptive nameGenz-682452-AU
    D.3.9.4EV Substance CodeSUB166602
    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 Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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 No
    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
    Gaucher disease
    E.1.1.1Medical condition in easily understood language
    Gaucher disease
    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 24.1
    E.1.2Level PT
    E.1.2Classification code 10075699
    E.1.2Term Gaucher's disease type III
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 24.1
    E.1.2Level PT
    E.1.2Classification code 10075697
    E.1.2Term Gaucher's disease type I
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Part 1:
    -Evaluate central nervous system (CNS) biomarkers in adult Gaucher disease (GD) type 3 that distinguish GD3 from adult Gaucher disease type 1 (GD1) patients.
    -Screen adult GD3 patients who qualify for treatment with
    venglustat in Parts 2,3 and Part 4

    Part 2 and 3: Combination treatment phases
    -Evaluate short-term (Part 2) and long-term (Part 3) safety and
    tolerability of GZ/SAR402671 in combination with Cerezyme in adult GD3 patients.
    -Evaluate the change in cerebrospinal fluid (CSF) CNS biomarkers (glucosylceramide [GL-1] and lyso-glucosylceramide [lyso-GL1]) from adult GD3 patients receiving GZ/SAR402671 in combination with Cerezyme (Part 2 only).
    Part 4: Extended treatment phase with monotherapy
    - Evaluate safety and tolerability of venglustat monotherapy in adult
    GD3 patients who have remained systemically stable on venglustat in
    combination with Cerezyme
    E.2.2Secondary objectives of the trial
    Parts 2 and 3: Combination treatment phases
    -Evaluate the pharmacokinetics of GZ/SAR402671 in adult GD3 patients (Part2).
    -Explore the efficacy of GZ/SAR402671 in combination with Cerezyme in infiltrative lung disease (IDL) in adult GD3 patients (Part 2 and 3).
    -Explore the efficacy of GZ/SAR402671 in combination with Cerezyme in systemic disease in adult GD3 patients (Part 2 and 3).
    -Explore the efficacy of GZ/SAR402671 in combination with Cerezyme in neurological function and on exploratory CSF biomarkers in adult GD3 patients (Part 2 and 3).
    - Explore plasma biomarkers (lyso-GL-1 and GL-1) in adult GD3 patients
    - Explore CSF biomarkers other than lyso-GL-1 and GL-1 in adult GD3
    patients (Part 2 only)
    Part 4: Extended treatment phase with monotherapy
    - Explore the efficacy of venglustat in systemic disease in adult GD3
    patients
    - Explore the efficacy of venglustat on neurological function in adult GD3
    patients
    - Explore plasma biomarkers (lyso-GL-1 and GL-1) in adult GD3 patients
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    -The patient must provide written informed consent prior to any studyrelated procedures being performed.
    -Has a clinical diagnosis of Gaucher Disease Type 1 (GD1) or Gaucher Disease Type 3 GD3 and documented deficiency of acid beta-glucosidase activity.
    -The patient has received treatment with enzyme repalcement therapy for at least 3 years. For at least 6 months prior to enrollment, the Patient has received Cerezyme at a stable monthly dose and must continue at the same monthly dose during the study.
    -The patient has reached Gaucher disease therapeutic goals defined as all of the following to be eligible for this study:
    -Hemoglobin level of ≥11.0 g/dL for females and ≥12.0 g/dL for males.
    -Platelet count ≥100 000/mm^3.
    -Spleen volume <10 multiples of normal (MN)MN), or total splenectomy (provided the splenectomy occurred >3 years prior to randomization).
    -Liver volume <1.5 MN.
    -No bone crisis and free of symptomatic bone disease such as bone pain attributable to osteonecrosis and/or pathological fractures within 3 months prior to screening.
    - The patient has maintained GD therapeutic goals defined as all of the following to be eligible for entering Part 4 of this study:
    - Hemoglobin level of ≥11.0 g/dL for females and ≥12.0 g/dL for males
    - Platelet count ≥100,000/mm3
    - Spleen volume <10 multiples of normal (MN), or total splenectomy
    - Liver volume <1.5 MN
    - No bone crisis and free of symptomatic bone disease such as bone pain attributable to osteonecrosis and/or pathological fractures within 3 months prior to entering Part 4
    - The patient, if female and of childbearing potential must have a negative pregnancy test (urine beta-human chorionic gonadotropin [β-hCG]) at baseline.
    -If the patient has a history of seizures, except for myoclonic seizures, they are well controlled under appropriate medication not identified as a strong or moderate inducer or inhibitor of CYP3A.
    Adult GD1 cohort only:
    -GD1 patient is ≥18 and ≤40 years of age.
    Adult GD3 cohort only:
    -GD3 patient is ≥18 years of age.
    -The patient is willing to abstain from consumption of grapefruit, grapefruit juice, or grapefruit containing products for 72 hours prior to administration of the first dose of GZ/SAR402671 and for the duration of the 156 week treatment period.
    -Oculomotor apraxia characterized by a horizontal saccade abnormality.
    -Cerezyme treatment every 2 weeks (minimum dose 30 U/kg every 2 weeks).
    -Females patients of childbearing potential and males patients must be willing to practice true abstinence in line with their preferred and usual lifestyle, or use 2 acceptable effective methods of contraception for the duration of the study and for at least 6 weeks for females and 90 days for males following their last dose of study drug.
    E.4Principal exclusion criteria
    -Substrate reduction therapy or chaperone therapy for GD within 6 months prior to enrollment.
    -The patient has had a partial or total splenectomy within 3 years Prior to randomization.
    -The patient is blood transfusion-dependent.
    -Prior esophageal varices or liver infarction or current liver enzymes (alanine aminotransferase [ALT]/aspartate aminotransferase [AST]) or total bilirubin >2 times the upper limit of normal, unless the patient has a diagnosis of Gilbert Syndrome.
    -Clinically significant congenital cardiac defect, coronary artery disease, valve disease or left sided heart failure; clinically significant arrhythmias or conduction defect.
    -The patient has any clinically significant disease, other than GD, including cardiovascular, renal, hepatic, gastrointestinal, pulmonary, neurologic, endocrine, metabolic (eg, hypokalemia, hypomagnesemia), or psychiatric disease, other medical conditions, or serious intercurrent illnesses that may preclude participation.
    -The patient has received an investigational product within 30 days Prior to enrollment.
    -The patient has a history of cancer, with the exception of basal cell carcinoma.
    -The patient has myoclonic seizures.
    -The patient is pregnant or lactating.
    -The patient has, according to World Health Organization (WHO) Grading, a cortical cataract >onequarter of the lens circumference (Grade cortical cataract-2) or a posterior subcapsular cataract >2 mm (Grade posterior subcapsular cataract-2). Patients with nuclear cataracts will not be excluded.
    -The patient requires use of invasive ventilatory support.
    -The patient requires use of noninvasive ventilator support while awake for longer than 12 hours daily.
    -The patient is unable to receive treatment with Cerezyme due to a known hypersensitivity or is unwilling to receive Cerezyme Treatment every 2 weeks.
    -The patient is currently receiving potentially cataractogenic medications as listed in Section 8.8.2.
    -The patient has received strong or moderate inducers or inhibitors of Cytochrome p450 Isoform 3A within 30 days or 5 half-lives from screening, whichever is longer, prior to enrolment in Part 2. This also includes the consumption of grapefruit, grapefruit juice, or Grapefruit containing products within 72 hours of starting GZ/SAR402671 administration in Parts 2 and 3.
    -The patient is scheduled for in-patient hospitalization including elective surgery, during the study.
    -Has had a major organ transplant (eg, bone marrow or liver).
    -The patient, in the opinion of the Investigator, is unable to adhere to the requirements of the study or unable to undergo study assessments (e.g., contraindications for magnetic resonance imaging).
    E.5 End points
    E.5.1Primary end point(s)
    1) Number of patients with adverse events
    2) Assessment of pharmacodynamic (PD) parameter: Lysoglucosylceramide
    (lyso-GL1) and glucosylceramide (GL-1) in
    cerebrospinal fluid (CSF) ; Change from baseline in CSF lyso-GL1 and GL1
    E.5.1.1Timepoint(s) of evaluation of this end point
    1 - From screening up to end of study, up to approximately 8.7 years

    2 - From screening through Week 52
    E.5.2Secondary end point(s)
    1 - Assessment of pharmacodynamic (PD) parameter: Lysoglucosylceramide
    (lyso-GL1) and glucosylceramide (GL-1) in plasma ;
    Change from baseline in plasma lyso-GL1 and GL1
    2 - Assessment of plasma pharmacokinetic parameter: Cmax ; Plasma
    maximum concentration (Cmax)
    3 - Assessment of plasma pharmacokinetic parameter: Tmax ; Plasma
    time at Cmax (Tmax)
    4 - Assessment of plasma pharmacokinetic parameter: AUC ;Plasma area
    under the curve (AUC)
    5 - Assessment of plasma pharmacokinetic parameter: Ctrough ; Plasma
    trough concentration (Ctrough)
    6 - Assessment of CSF pharmacokinetic parameter: Cmax ; CSF maximum
    concentration (Cmax)
    7 - Assessment of pharmacokinetic parameter: CSF time at Cmax (Tmax)
    8 - Assessment of pharmacokinetic parameter: CSF area under the curve
    (AUC)
    E.5.2.1Timepoint(s) of evaluation of this end point
    1 - From screening up to end of study, up to approximately 8.7 years
    2, 3, 4, 6, 7, 8 - Day 1, Week 4, Week 26, and Week 52
    5 - Weeks 12 and 39 (Part 2), and on Weeks 78, 104, and 156 (for Part
    3)
    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 Yes
    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.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA2
    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
    Japan
    United Kingdom
    United States
    Germany
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years8
    E.8.9.2In all countries concerned by the trial months7
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    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) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 18
    F.1.3Elderly (>=65 years) No
    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 No
    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 6
    F.4.2.2In the whole clinical trial 18
    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)
    Eligible patients may enter an extension trial. Patients will remain on Cerezyme as standard treatment of care
    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 Decision2016-09-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-10-20
    P. End of Trial
    P.End of Trial StatusOngoing
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