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    Summary
    EudraCT Number:2014-002053-19
    Sponsor's Protocol Code Number:CLMI070X2201
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:
    Date on which this record was first entered in the EudraCT database:2014-11-27
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2014-002053-19
    A.3Full title of the trial
    An open-label multi-part first-in-human study of oral LMI070 in infants with Type 1 spinal muscular atrophy
    Open-label eerste onderzoek bij de mens dat bestaat uit meerdere onderdelen met LMI070 drank bij baby’s met type 1 spinale spieratrofie
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clinical trial of LMI070 given by mouth to Type I SMA infant patients
    Onderzoek met LMI070 drank bij baby’s met type 1 spinale spieratrofie
    A.3.2Name or abbreviated title of the trial where available
    CLMI070X2201
    CLMI070X2201
    A.4.1Sponsor's protocol code numberCLMI070X2201
    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 SponsorNovartis Pharma Services AG
    B.1.3.4CountrySwitzerland
    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 supportNovartis Pharma services AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNovartis Pharma Services AG
    B.5.2Functional name of contact pointClinical Trial Information Desk
    B.5.3 Address:
    B.5.3.1Street AddressLichtstrasse 35
    B.5.3.2Town/ cityBazel
    B.5.3.3Post code4056
    B.5.3.4CountrySwitzerland
    B.5.4Telephone number+4461324 1111
    B.5.5Fax number+4461324 8001
    B.5.6E-mailclinicaltrial.enquiries@novartis.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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code LMI070
    D.3.4Pharmaceutical form Oral solution
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLMI070
    D.3.9.2Current sponsor codeLMI070
    D.3.9.4EV Substance CodeSUB166489
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number3.5
    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
    Spinal Muscular Atrophy
    Spinale spieratrofie
    E.1.1.1Medical condition in easily understood language
    motor neuron disease
    motor neuron ziekte
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    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
    To determine the safety and tolerability of ascending weekly doses and estimate the MTD of oral/enteral LMI070 in infants with type 1 SMA.
    Part 2
    To evaluate the safety and tolerability of multiple dose weekly regimens of oral/enteral LMI070 for 12 weeks in patients with type 1 SMA.
    Deel 1
    De veiligheid en verdraagbaarheid van toenemende wekelijkse doses te bepalen en de MTD van oraal/enteraal LMI070 bij baby’s met type 1 SMA te schatten.
    Deel 2
    De veiligheid en verdraagbaarheid van meerdere dosisschema’s van oraal/enteraal LMI070 te evalueren gedurende 12 weken bij patiënten met type 1 SMA.
    E.2.2Secondary objectives of the trial
    Part 1
    -To evaluate LMI070 pharmacokinetics in serum after single and repeated doses of LMI070.
    -To evaluate the effect of LMI070 on muscle by ultrasound.
    -To evaluate the effect of LMI070 on growth parameters.
    -To evaluate the effect of LMI070 on respiratory function
    -To evaluate the effect of LMI070 on infant motor development.

    Part 2:
    -To evaluate the efficacy of LMI070 on motor and developmental milestones
    -To evaluate the efficacy of LMI070 on ulnar nerve compound action potential [CMAP] (optional)
    Deel 1
    - De farmacokinetiek van LMI070 in het serum evalueren na één dosis en herhaalde doses van LMI070.
    - Het effect van LMI070 op de spier evalueren op basis van echografie.
    - Het effect van LMI070 op groeiparameters evalueren
    - Het effect van LMI070 op de ademhalingsfunctie evalueren
    - Het effect van LMI070 op de motorische ontwikkeling van de baby evalueren.

    Deel 2
    - De werkzaamheid van LMI070 op mijlpalen van de motoriek en ontwikkeling evalueren
    - De werkzaamheid van LMI070 op de samengestelde actiepotentiaal (compound muscle action potential; CMAP) van de nervus ulnaris evalueren (optioneel)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Written informed consent must be obtained from the parent / guardian before any assessment is performed.
    - Type 1 SMA, diagnosed clinically (symptom onset <6 months of age) and confirmed genetically (homozygous SMN1 gene deletion or mutation) plus SMN2 copy number of 2.
    - Best supportive care in place and stable for at least 14 days before screening.
    - Age at screening between 1 and 7 months, plus or minus 2 weeks.
    - Must be able to demonstrate antigravity strength in both biceps.
    - Must have or agree to have placement of feeding tube for enteral access via nasogastric (NG), nasojejunal (NJ), percutaneous gastrostomy (PEG), or percutaneous jejunostomy (PEJ) tube.
    - Er moet een schriftelijke toestemming zijn verkregen van de ouderr/voogd voordat er onderzoeksprocedures worden uitgevoerd.
    - Type 1 SMA, klinisch gediagnostiseerd (ontstaan van symptomen <6 maanden oud) en genetisch bevestigd (homozygote deletie of mutatie van SMN1-gen) plus 2 kopieën van SMN2.
    - Aanwezigheid goede ondersteunende zorg en is stabiel gedurende ten minste 14 dagen vóór de screening.
    - Leeftijd bij screening tussen 1 en 7 maanden ± 2 weken.
    - Moet in staat zijn aan te tonen dat beide biceps sterker zijn dan de zwaartekracht.
    - Moet een voedingssonde hebben of instemmen met de plaatsing daarvan voor enterale toegang via een nasogastrische (NG), nasojejunale (NJ), percutane gastrostomie (PEG) of percutane jejunostomiesonde (PEJ).
    E.4Principal exclusion criteria
    - Use of other investigational drugs within 14 days.
    - Neurologic, neuromuscular or genetic disorders other than SMA
    - Anemia (Hgb < 8 g/dL), leukopenia (ANC < 2000/ml), or thrombocytopenia (< 100,000/mL).
    - Hepatic dysfunction (AST or ALT > 1.5 x ULN; total bilirubin > ULN).
    - Renal dysfunction (eGFR < 80 ml/min).
    - Clinically significant abnormalities in hematology or clinical chemistry parameters, as assessed by the Site Investigator, at screening that would render the subject unsuitable for inclusion
    - Hypoxemia (O2 saturation awake <92% or O2 saturation asleep <91%,without ventilation support) or requiring oral suctioning >2 per day
    - Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy at any time during the screening period.
    - Excluding SMA, any medically unstable condition including cardiomyopathy, hepatic dysfunction, kidney disorder, endocrine disorder, GI disorders, prematurity of <32 weeks gestation, metabolic disorders, severe respiratory compromise and significant brain abnormalities or injuries including hypoxic-ischemic encephalopathy.
    - Ongoing medical condition that according to the Site Investigator would interfere with the conduct and assessments of the study. Examples are medical disability other than SMA that would interfere withthe assessment of safety or would compromise the ability of the subject to undergo study procedures including be assessed by CHOP-INTEND motor scale.
    - Gebruik van andere onderzoeksmiddelen binnen 14 dagen.
    - Andere neurologische, neuromusculaire of genetische aandoeningen dan SMA.
    - Anemie (Hb <8 g/dl), leukopenie (absolute neutrofielentelling < 2000/ml) of trombocytopenie (< 100.000/ml).
    - Leverinsufficiëntie (ASAT of ALAT > 1,5 x bovengrens van de normaalwaarde; totale bilirubine > bovengrens van de normaalwaarde).
    - Nierinsufficiëntie (eGFR < 80 ml/min).
    - Klinisch significante afwijkingen in parameters van de hematologie of klinische chemie bij de screening, zoals beoordeeld door de onderzoeker van het centrum, die de proefpersoon ongeschikt zouden maken voor inclusie
    - Hypoxemie (zuurstofverzadiging wakker <92% of zuurstofverzadiging in slaap <91% zonder ondersteuning van een beademingsapparaat) of orale suctie >2 keer per dag nodig
    - Aanwezigheid van een onbehandelde of onvoldoende behandelde actieve infectie waarvoor een systemische antivirale of antibacteriële behandeling nodig is op enig moment tijdens de screeningperiode.
    - Een medisch onstabiele aandoening, met uitzondering van SMA, waaronder cardiomyopathie, leverinsufficiëntie, nieraandoening endocriene stoornis, maag-darmstelselaandoeningen, prematuur geboren (<32 weken zwangerschap), stofwisselingsstoornissen, ernstige ademhalingsproblemen en belangrijke hersenafwijkingen of hersenletsel waaronder hypoxisch-ischemische encefalopathie.
    - Huidige medische aandoening die naar het oordeel van de onderzoeker van het centrum de uitvoering en beoordelingen van het onderzoek zou verstoren. Voorbeelden hiervan zijn een medische handicap (met uitzondering van SMA) die de beoordeling van de veiligheid zou verstoren of het vermogen van de proefpersoon om onderzoeksprocedures te ondergaan negatief zou beïnvloeden, waaronder evaluatie aan de hand van de CHOP-INTEND motoriekschaal.
    E.5 End points
    E.5.1Primary end point(s)
    Primary endpoints Part 1:
    Physical Exam: Screening, D1 – D85 + EOS
    Vital signs: Screening, D1 – D85 + EOS
    ECG: Screening, D1, D8, D85 + EOS
    Safety: Screening, Baseline, D3, D8, D15, D29, D43, D57, D71, D85 + EOS
    Adverse Events: All Visits

    Primary endpoints Part 2:
    Physical Exam: Screening, Baseline, D1 – D88 + EOS
    Vital signs: Screening, Baseline, D1 – D88 + EOS
    ECG: Screening, D1, D8, D88 + EOS
    Safety: Screening, Baseline, D8, d15, D2, D29, D36, D43, D50, D57, D64, D71, D88 + EOS
    Adverse Events: All Visits
    Primaire eindpunten Deel 1:
    Lichamelijk onderzoek: Screening, D1 - D85 + EOS
    Vitale functies: Screening, D1 - D85 + EOS
    ECG: Screening, D1, D8, D85 + EOS
    Veiligheid: Screening, Baseline, D3, D8, D15, D29, D43, D57, D71, D85 + EOS
    Bijwerkingen: Alle bezoeken

    Primaire eindpunten Deel 2:
    Lichamelijk onderzoek: Screening, Baseline, D1 - D88 + EOS
    Vitale functies: Screening, Baseline, D1 - D88 + EOS
    ECG: Screening, D1, D8, D88 + EOS
    Veiligheid: Screening, Baseline, D8, D15, D2, D29, D36, D43, D50, D57, D64, D71, D88 + EOS
    Bijwerkingen: Alle bezoeken
    E.5.1.1Timepoint(s) of evaluation of this end point
    See Above (E.5.1)
    Zie hierboven (E.5.1)
    E.5.2Secondary end point(s)
    Secondary Endpoints Part 1:
    PK: D1 (Pre-dose + 1, 2, 4, 8 & 24 hours post-dose), D2, D3, D5, D8, D29, D43
    Ultrasound: Baseline, D85 + EOS
    Growth measurements: Screening, D1, D8-D85 + EOS
    Respiratory function: Baseline, D8-D85 +EOS
    CHOP-INTEND: Baseline, D36, D85 + EOS

    Secondary Endpoints Part 2:
    PK: D1 (Pre-dose + 1, 2, 4, 8 & 24 hours post-dose), D2, D3, D5, D8, D29, D43, D57 (Pre-dose + 2, 4, 8 & 24 hours post-dose), D59, D62
    Ultrasound: Baseline, D88 + EOS
    Growth measurements: Screening, D1, D8-D57, D64, D71, D88 + EOS
    Respiratory function: Baseline, D8-D57, D64, D71, D88 + EOS
    CHOP-INTEND: Baseline, D15, D36, D57, D88 + EOS
    CMAP: Baseline, D88 + EOS
    Secundaire eindpunten Deel 1:
    PK: D1 (Pre-dosis + 1, 2, 4, 8 en 24 uur na toediening), D2, D3, D5, D8, D29, D43
    Echografie: Baseline, D85 + EOS
    Groei metingen: Screening, D1, D8-D85 + EOS
    Ademhalingsfunctie: Baseline, D8-D85 + EOS
    CHOP-PLAN: Baseline, D36, D85 + EOS

    Secundaire eindpunten Deel 2:
    PK: D1 (Dalconcentraties + 1, 2, 4, 8 en 24 uur na toediening), D2, D3, D5, D8, D29, D43, D57 (Dalconcentraties + 2, 4, 8 en 24 uur na -dose), D59, D62
    Echografie: Baseline, D88 + EOS
    Groei metingen: Screening, D1, D8-D57, D64, D71, D88 + EOS
    Longfunctie: Baseline, D8-D57, D64, D71, D88 + EOS
    CHOP-PLAN: Baseline, D15, D36, D57, D88 + EOS
    CMAP: Baseline, D88 + EOS
    E.5.2.1Timepoint(s) of evaluation of this end point
    See above (E.5.2)
    Zie hierboven (E.5.2)
    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 No
    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 No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Tolerability
    Verdraagbaarheid
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans Yes
    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.8.3 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 EEA8
    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
    Belgium
    Denmark
    Germany
    Italy
    Netherlands
    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
    LVLS
    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 months10
    E.8.9.1In the Member State concerned days15
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 22
    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: 22
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    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 No
    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
    infants
    baby's
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state2
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 20
    F.4.2.2In the whole clinical trial 22
    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)
    Patients will initially be treated for 13 weeks, however dosing may be extended if recommended by the independent DMC.
    Patiënten zullen in eerste instantie worden behandeld voor 13 weken, maar de dosering kan worden verlengd indien aanbevolen door de onafhankelijke DMC.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2014-11-24
    N.Ethics Committee Opinion of the trial application
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion
    P. End of Trial
    P.End of Trial Status
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