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    EudraCT Number:2012-004040-30
    Sponsor's Protocol Code Number:EOC.NSI.11.01
    National Competent Authority:Austria - BASG
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2013-03-12
    Trial results
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedAustria - BASG
    A.2EudraCT number2012-004040-30
    A.3Full title of the trial
    Natalizumab de-escalation to interferon-beta-1b in patients with
    relapsing-remitting multiple sclerosis: A multicenter study
    Natalizumab Deeskalation mit Interferon-beta-1b bei Patienten mit
    schubförmiger Multipler Sklerose - eine multizentrische Studie
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Natalizumab de-escalation to interferon-beta-1b in patients with
    relapsing-remitting multiple sclerosis: A multicenter study
    Natalizumab Deeskalation mit Interferon-beta-1b bei Patienten mit
    schubförmiger Multipler Sklerose - eine multizentrische Studie
    A.4.1Sponsor's protocol code numberEOC.NSI.11.01
    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 SponsorOspedale Regionale di Lugano
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportBayer HealthCare
    B.4.1Name of organisation providing supportBayer HealthCare
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationOspedale Regionale di Lugano
    B.5.2Functional name of contact pointDepartment of Neurology
    B.5.3 Address:
    B.5.3.1Street AddressVia Tesserete 46
    B.5.3.2Town/ cityLugano
    B.5.3.3Post code6903
    B.5.4Telephone number0043918116474
    B.5.5Fax number0043918116219
    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 Yes
    D. name BETAFERON® (interferon beta-1b)
    D. of the Marketing Authorisation holderBayer Pharma AG
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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.3.1Product nameBetaferon
    D.3.4Pharmaceutical form Powder and solution for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBetaferon
    D.3.9.1CAS number 145155-23-3
    D.3.9.3Other descriptive nameINTERFERON BETA-1B
    D.3.9.4EV Substance CodeSUB12432MIG
    D.3.10 Strength
    D.3.10.1Concentration unit µg/ml microgram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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
    relapse-remitting multiple sclerosis
    schubförmige Multiple Sklerose
    E.1.1.1Medical condition in easily understood language
    Multiple Sclerosis
    Multiple Sklerose
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the concept of natalizumab de-escalation to
    interferon-beta-1b e.o.d in relapsing-remitting multiple sclerosis
    patients, who consider stopping natalizumab due to a benefit-risk
    assessment. In particular, to evaluate if interferon beta-1b
    treatment may be able to overcome the recurrence of significant
    clinical and radiological disease activity after natalizumab
    cessation and keep disease activity better under control as
    compared to the time prior to natalizumab.
    E.2.2Secondary objectives of the trial
    not applicable
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    · Female or male patients with relapsing-remitting forms of multiple
    sclerosis (according to McDonald's criteria);
    · Age between 18 and 70 years;
    · Natalizumab-treatment for at least 12 months following the current Swiss guidelines for treatment initiation;
    · Treated with a disease-modifying therapy other than interferon beta-1b for at least 12 months before natalizumab was initiated;
    · Never treated with interferon beta-1b;
    · Eligible patients are clinically stable (free from relapses and 6-month confirmed disability progression for at least 6 months) while on natalizumab-treatment and do not show any Gd-enhancement on their last MRI performed while on Tysabri;
    · In eligible patients MRI were performed in the past as following
    a) 6-18 months prior to natalizumab-treatment
    b) at natalizumab start
    c) 12 months after natalizumab initiation;
    · Good records with regard to clinical disease activity (relapse rate,
    EDSS progression) in the year prior to natalizumab and during
    · Patients who decide to stop natalizumab treatment after a careful
    benefit/risk assessment. Risk for PML increases with duration of
    natalizumab exposure, pretreatment with an immunosuppressant
    agent or serological status of anti-JC-virus positivity;
    · Patients, who in context with cessation of natalizumab have decided, after a careful benefit/risk assessment, to continue treatment of their MS with Interferon beta-1b;
    · Women of potential childbearing with active contraceptive methods;
    · Patients who are willing to undergo study procedures;
    · Patients who are willing to undergo MRI;
    · Patients who are willing and able to sign informed consent.
    • Männer und Frauen mit der Diagnose einer schubförmigremittierenden
    Multiplen Sklerose;
    • Alter zwischen 18 und 70 Jahren;
    • Behandlung mit Natalizumab während mindestens 12 Monaten
    gemäss den schweizerischen und österreichischen Leitlinien betreffend
    den Beginn einer solchen Therapie;
    • Behandlung mit einer anderen Therapie erster Linie als Interferon
    Beta-1b während mindestens 12 Monaten vor dem Beginn der
    Behandlung mit Natalizumab;
    • keine vorhergehende Therapie mit Interferon Beta-1b;
    • klinische Stabilität (keine Schübe und/oder
    Behinderungsprogression bestätigt während mindestens 6 Monaten
    während der Behandlung mit Natalizumab, keine neuen
    Gadoliniumanreichernden Lesionen in der letzten Magnetresonanz,
    welche während der Behandlung mit Natalizumab durchgeführt
    • Verfügbarkeit vertrauenswürdiger und vollständiger betreffend
    vorausgehender Krankheitsaktivität (Rückfallquote,
    Behinderungsprogression bestimmt mit EDSS) im Jahr vor und
    während der Natalizumabtherapie;
    • Entscheid zur Beendigung der Natalizumabtherapie nach einer
    angemessenen Nutzen-/Risikobestimmung (Patienten mit langer
    Therapiedauer, vorhergehender immunsuprimierender Therapie,
    positiven AK-anti-JC-Virus haben ein höheres Risiko der progressiven
    multifokalen Leukenzephalopathie);
    • Patienten, die im Rahmen der Unterbrechung der Behandlung mit
    Natalizumab nach einer angemessenen Nutzen-/Risikobestimmung
    entschieden haben, ihre MS mit Interferon Beta 1-b weiter zu
    • Frauen in gebärfähigem alter mit aktiver kontrazeptiver Methode;
    • Patienten, welche mit dem Studienablauf einschliesslich der
    Magnetresonanz einverstanden sind;
    • Patienten, welche einverstanden sind teilzunehmen und die
    Fähigkeit haben, die Einverständniserklärung zu verstehen und zu
    E.4Principal exclusion criteria
    · Patients who have previously entered this study;
    · Natalizumab-treatment for less than 12 months following the current Swiss guidelines for treatment initiation;
    · Prior treatment with interferon beta-1b (ever interferon beta-1b);
    · Sign of clinical disease activity within the 6 months;
    · One or more relapses and/or 6-month confirmed disability
    progression during the 6 months prior to the study;
    · Secondary progressive MS;
    · Primary progressive MS;
    · Pregnancy - Serum pregnancy test at screening visit positive- or
    breast feeding;
    · Uncontrolled, clinically significant heart diseases, such as
    arrhythmias, angina, or uncompensated congestive heart failure;
    · History of severe depression or attempted suicide or current suicidal
    · Medical or psychiatric conditions that compromise the ability to give informed consent, to comply with the protocol, or to complete the study;
    · Uncontrolled seizure disorder;
    · Myopathy or clinically significant liver disease;
    · Inability, in the opinion of the principal investigator or staff, to comply with protocol requirements for the duration of the study;
    · Known hypersensitivity to interferon-beta or other human proteins including albumin;
    · Any contraindication for MRI or contrast administration;
    · A history of drug abuse in the 6 months prior to screening;
    · Treatment with any of the following in the 30 days before day 1:
    systemic corticosteroids, ACTH, or other investigational drugs;
    · Participation in any other study involving investigational or marketed products, concomitantly or within 30 days prior to entry in the study;
    · Current participation on other clinical trials;
    · Treatment with drugs which might interfere with the evaluation of
    study drugs during the study protocol such as immunomodulants,
    immunosuppressives other than interferon beta-1b;
    · Likelihood of requiring treatment during the study period with drugs not permitted by the study protocol such as immunomodulants, immunosuppressives other than interferon beta-1b.
    • Patienten, welche bereits in diese Studie eingeschlossen sind;
    • Behandlungsdauer mit Natalizumab weniger als 12 Monate;
    • Vorhergehende Behandlung mit Interferon Beta-1b;
    • klinische Zeichen der Krankheitsaktivität während der letzten 6
    Monate (eine oder mehrere Schübe und/oder Behinderungsprogression bestätigt nach 6 Monaten);
    • Patienten mit primär oder sekundär progressiver Multipler Sklerose;
    • bestehende Schwangerschaft (Schwangerschaftstest anlässlich des Screenings) oder stillende Mütter;
    • klinisch signifikante kardiovaskuläre Krankheiten, welche nicht
    kontrolliert sind, mit Arrhythmien, Angina pectoris oder
    dekompensierter, kongestiver Herzinsuffizienz;
    • vorhergehende oder bestehende schwere Depression oder
    Suizidversuch oder bestehende suizidale Ideen;
    • allgemeinmedizinische oder psychiatrische Einschränkungen, welche das Erbringen der Einverständniserklärung, das Folgen des
    Studienprotokolls oder die Beendigung der Studie verhindern können;
    • nicht kontrollierte Epilepsie;
    • klinisch signifikante Myopathie oder Hepatopathie;
    • Unfähigkeit, sich während der Studiendauer an das Studienprotokoll zu halten, sei es aufgrund personeller oder nach Einschätzung des untersuchenden Arztes;
    • bekannte Unverträglichkeit von Interferon Beta-1b oder
    menschlicher Proteine einschliesslich Albumin;
    • jegliche Kontraindikation zur Durchführung von Magnetresonanzen oder der Verabreichung von Kontrastmitteln zur Durchführung der Magnetresonanz;
    • Bekannter Substanzabusus in den 6 Monaten vor dem
    • Therapie mit einem der folgenden Medikamente 30 Tage vor
    Studienbeginn: systemische Kortikosteroide, ACTH, andere
    Medikamente welche sich noch in klinischen Studien befinden;
    • Teilnahme an anderen klinischen Studien, aktuell und in den 30
    Tagen vor Studienbeginn;
    • Einnahme anderer Therapien, welche das Studienmedikament
    beeinflussen könnten;
    • hohe Wahrscheinlichkeit des Bedarfs eines während der Studie
    verbotenen Medikaments.
    E.5 End points
    E.5.1Primary end point(s)
    Primary endpoint:
    Annualized relapse rate on study after treatment with interferon beta 1b compared to annualized relapse rate in the year prior to
    natalizumab initiation on first line disease modifying treatment.
    Primärer Endpunkt:
    Inzidenz der jährlichen Schubrate während der Studie im Vergleich mit derjenigen im während dem Jahr vor Beginn der Natalizumabtherapie
    E.5.1.1Timepoint(s) of evaluation of this end point
    Primary endpoint:
    Annualized relapse rate on study after 12 months of treatment with interferon beta 1b (Assessments: Day 1, month 3, 6, 9, 12)
    compared to annualized relapse rate in the year prior to natalizumab initiation on first line disease modifying treatment (month -24 to -12).
    E.5.2Secondary end point(s)
    Secondary endpoints:
    1) Change of clinical parameters (severity of relapses by functional
    system score, proportion of relapse-free patients), 3-month confirmed EDSS progression (of at least 1.0 points if score < 5.5, at least 0.5 points if score ≥ 5.5), MSFC compared to baseline.
    2) Change of EDSS, MSFC scores from baseline to 12 months
    compared to the changes in the year prior to natalizumab treatment.
    3) MRI parameters (number of new T2-hyperintense lesions, number of Gd-enhancing lesions on T1-weighted images) with subtraction MRI.
    4) Patient reported outcome: Quality of life using EQ-5D, Functional assessment of multiple sclerosis (FAMS).
    Sekundäre Endpunkte:
    1) Klinische Parameter: Schweregrad der Schübe, Anzahl der Patienten ohne Schübe, Behinderungsprogression (EDSS) bestätigt nach 3
    Monaten (Erhöhung des EDSS um mindestens 1.0 Punkte ausgehend von einem EDSS < 5.5, um mindestens 0.5 Punkte bei EDSS ≥5.5).
    2) Beurteilung des Behinderungsgrades alle 3 Monate mittels MSFC.
    3) Parameter der alle 6 Monate durchgeführten Magnetresonanz:
    Anzahl neuer hyperintenser Läsionen in den T2-Sequenzen, ermittelt mittels der Bildsubstraktionsmethode, Anzahl
    Gadoliniumanreichernder Läsionen in den T1-Sequenzen.
    4) Patientenfragebogen: Lebensqualität EQ-5D, FAMS
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary endpoints:
    Change of clinical parameters (severity of relapses by functional
    system score, proportion of relapse-free patients), 3-month
    confirmed EDSS progression (of at least 1.0 points if score < 5.5, at least 0.5 points if score ≥ 5.5), MSFC at months 3, 6, 9, 12, 15, 18, 21, 24 compared to baseline (Day 1).
    Change of EDSS, MSFC scores from baseline to 12 months
    compared to the changes in the year prior to natalizumab treatment (month -24 to -12).
    MRI parameters (number of new T2-hyperintense lesions, number of Gd-enhancing lesions on T1-weighted images) with subtraction MRI at months 6,12, 24.
    Patient reported outcome
    Quality of life using EQ-5D, Functional assessment
    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 No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    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. trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    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 concerned3
    E.8.5The trial involves multiple Member States No
    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
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    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 years3
    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: 36
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 36
    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 Information not present in EudraCT
    F.4 Planned number of subjects to be included
    F.4.1In the member state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 12
    F.4.2.2In the whole clinical trial 72
    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)
    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 Decision2013-04-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-05-24
    P. End of Trial
    P.End of Trial StatusOngoing
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