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    Summary
    EudraCT Number:2014-003198-40
    Sponsor's Protocol Code Number:DFI13803
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-08-07
    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 ConcernedGermany - BfArM
    A.2EudraCT number2014-003198-40
    A.3Full title of the trial
    A Phase 1/2, Multi-Center, Open-Label, Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Exploratory Efficacy of Recombinant Human Acid Sphingomyelinase in Pediatric Patients Aged <18 Years With Acid Sphingomyelinase Deficiency

    Revised title further to the protocol amendment 1
    A phase 1/2, multi-center, open-label, ascending dose study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and exploratory efficacy of olipudase afa in pediatric patients aged <18 years with acid sphingomyelinase deficiency
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Safety, Tolerability, PK, and Efficacy Evaluation of Repeat Ascending Doses of rhASM in Pediatric Patients <18 Years of Age with Acid Sphingomyelinase Deficiency
    A.4.1Sponsor's protocol code numberDFI13803
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02292654
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/053/2015
    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 numberEU/3/01/056
    D.3 Description of the IMP
    D.3.1Product nameOlipudase alfa (rhASM)
    D.3.2Product code GZ402665
    D.3.4Pharmaceutical form Powder for concentrate for 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 INNOlipudase alfa
    D.3.9.1CAS number 927883-84-9
    D.3.9.2Current sponsor codeGZ402665
    D.3.9.3Other descriptive nameRECOMBINANT HUMAN ACID SPHINGOMYELINASE (rhASM)
    D.3.9.4EV Substance CodeSUB75088
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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
    Patients with acid sphingomyelinase deficiency (Niemann-Pick disease)
    E.1.1.1Medical condition in easily understood language
    Patients with Niemann-Pick 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 20.1
    E.1.2Level LLT
    E.1.2Classification code 10041515
    E.1.2Term Sphingomyelin lipidosis
    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 evaluate the safety and tolerability of olipudase alfa administered
    intravenously in pediatric patients every 2 weeks for 64 weeks.
    E.2.2Secondary objectives of the trial
    To characterize the pharmacokinetic profile and evaluate the
    pharmacodynamics and exploratory efficacy of olipudase alfa
    administered intravenously in pediatric patients every 2 weeks for up to 64 weeks
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    The patient and/or patient’s parent(s)/legal guardian(s) must provide written informed assent/consent prior to any protocol-related procedures being performed.
    The patient is aged 0 to <18 years of age on the date of informed assent/consent.
    The patient has documented deficiency of acid sphingomyelinase as measured in peripheral leukocytes, cultured fibroblasts, or lymphocytes.
    The patient has a spleen volume ≥5 multiples of normal (MN) measured by magnetic resonance imaging (MRI); patients who have had partial splenectomy will be allowed if the procedure was performed ≥1 year before screening and the residual spleen volume is ≥5 MN.
    The patient’s height is -1 Z-score or lower.
    A negative serum pregnancy test in female patients of childbearing potential.
    Female patients of childbearing potential and sexually active male patients must be willing to practice true abstinence in line with their preferred and usual lifestyle, or use 2 acceptable effective methods of contraception.
    E.4Principal exclusion criteria
    The patient has received an investigational drug within 30 days before study enrollment
    The patient has any of the following medical conditions:
    - An active, serious, intercurrent illness.
    - Active hepatitis B or hepatitis C infection.
    - Infection with human immunodeficiency virus (HIV).
    - Cirrhosis (determined by clinical evaluation).
    - Significant cardiac disease (eg, clinically significant arrhythmia, moderate or severe pulmonary hypertension or valvular dysfunction, or <40% left ventricular ejection fraction by echocardiogram).
    - Malignancy diagnosed within the previous 5 years (except basal cell carcinoma).
    - Any other extenuating circumstance that can significantly interfere with study compliance, including all prescribed evaluations and follow-up activities.
    The patient has acute or rapidly progressive neurological abnormalities.
    The patients is homozygous for SMPD1 gene mutations R496L, L302P, and fs330 or any combination of these 3 mutations.
    The patient has a delay of gross motor skills.
    The patient has had a major organ transplant (eg, bone marrow, liver).
    The patient requires use of invasive ventilatory support.
    The patient requires use of noninvasive ventilatory support while awake and for >12 hours a day.
    The patient, in the investigator’s opinion, is unable to adhere to the requirements of the study.
    The patient has a platelet count <60,000 /μL (based on the average of 2 screening samples obtained greater than 24 hours apart).
    The patient has alanine aminotransferase or aspartate aminotransferase >250 IU/L or total bilirubin>1.5 mg/dL.
    The patient has an international normalized ratio (INR) >1.5
    The patient is unwilling or unable to abstain from ingesting alcohol the day before through 3 days after each infusion of rhASM during the treatment period. Measuring alcohol concentration in blood is not required.
    The patient is scheduled during the study for in-patient hospitalization including elective surgery.
    The patient requires medication(s) that may decrease rhASM activity (eg, fluoxetine, chlorpromazine; tricyclic antidepressants [eg, imipramine, or desipramine]).
    The patient is breast-feeding.
    E.5 End points
    E.5.1Primary end point(s)
    Number of adverse events
    Clinically significant changes in laboratory parameters
    Clinically significant changes in physical examinations
    E.5.1.1Timepoint(s) of evaluation of this end point
    From screening through week 64
    E.5.2Secondary end point(s)
    Maximum concentration (Cmax)
    Area under the curve until the last measurable concentration (AUClast)
    Area under the curve extrapolated to infinity (AUC)
    Half-life (t1/2)
    Clearance (CL)
    Volume of distribution (Vss)
    Change in sphingomyelin levels
    Change in sphingomyelin metabolite levels
    E.5.2.1Timepoint(s) of evaluation of this end point
    With the first infusion at 0.3, 1.0 and 3.0 mg/kg and at Week 52

    - Maximum concentration (Cmax)
    - Area under the curve until the last measurable concentration (AUClast)
    - Area under the curve extrapolated to infinity (AUC)
    - Half-life (t1/2)
    - Clearance (CL)
    - Volume of distribution (Vss)

    From Day 1 through Week 64

    - Change in sphingomyelin levels
    - Change in sphingomyelin metabolite levels
    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.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 Information not present in EudraCT
    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 EEA5
    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
    Brazil
    France
    Germany
    Italy
    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
    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 months10
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months10
    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: 20
    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: 2
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 14
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 4
    F.1.2Adults (18-64 years) No
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Given the rarity of acid sphingomyelinase deficiency (ASMD) and that patients with the non-neuronopathic form of the disease can be diagnosed as early as birth, the age for the study includes patients from birth to <18 years of age.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 11
    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)
    Following DFI13803 patients have the opportunity to enroll into the extension study (LTS13632) which will last up to an additional 4 years.

    Subsequently, depending on trial results and whether a marketing authorisation for olipudase alfa is granted, the sponsor will decide to either transition patients to commercial treatment or continue patients on investigational treatment or to discontinue treatment.
    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 Decision2015-09-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-10-06
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-12-09
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