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    Summary
    EudraCT Number:2019-003127-38
    Sponsor's Protocol Code Number:NL71001.029.19
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-04-09
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2019-003127-38
    A.3Full title of the trial
    Efficacy of add-on high dose simvastatin on markers for disease progression in MS patients treated with ocrelizumab and natalizumab (SIMSON), a phase II clinical trial.
    Effectiviteit van add-on hoge dosis simvastatine op markers voor ziekte progressie bij MS patiënten die behandeld worden met ocrelizumab en natalizumab (SIMSON), een fase II klinische trial.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Research on the effect of add-on high dosage simvastatin treatment on progression in MS patients treated with ocrelizumab and natalizumab.
    Onderzoek naar het effect van het toevoegen van hoge dosis simvastatine op progressie van MS patiënten die behandeld worden met ocrelizumab en natalizumab.
    A.3.2Name or abbreviated title of the trial where available
    SIMSON trial
    SIMSON studie
    A.4.1Sponsor's protocol code numberNL71001.029.19
    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 SponsorVUmc Neurology Department
    B.1.3.4CountryNetherlands
    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 supportStichting MS Research
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMS Center Amsterdam
    B.5.2Functional name of contact pointInvestigators Office
    B.5.3 Address:
    B.5.3.1Street AddressDe Boelelaan 1117
    B.5.3.2Town/ cityAmsterdam
    B.5.3.3Post code1081HV
    B.5.3.4CountryNetherlands
    B.5.4Telephone number00310204440717
    B.5.6E-mailz.vanlierop@amsterdamumc.nl
    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.2.1.2Country which granted the Marketing AuthorisationNetherlands
    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 nameSimvastatin
    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.3.8INN - Proposed INNSIMVASTATIN
    D.3.9.2Current sponsor codeSIMSON71001
    D.3.9.3Other descriptive nameSimvastatine
    D.3.9.4EV Substance CodeSUB10529MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    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
    Multiple sclerosis
    Multiple sclerose
    E.1.1.1Medical condition in easily understood language
    Multiple sclerosis
    Multiple sclerose
    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 assess the efficacy of add-on high-dose simvastatin in MS patients treated with natalizumab or ocrelizumab for at least six months on whole brain atrophy rate.
    Onderzoeken van de effectiviteit van add-on hoge dosis simvastatine bij MS patiënten die ten minste 6 maanden met natalizumab of ocrelizumab behandeld worden op de hersenatrofie snelheid.
    E.2.2Secondary objectives of the trial
    1. To investigate the effect of add-on high-dose simvastatin in the above mentioned patient population on regional grey and white matter volumes.
    2. To explore the potential of serum NfL as predictor of treatment response and disease progression.
    3. To investigate the effect on clinical, other imaging and patient reported outcome measures of disability progression of add-on high-dose simvastatin treatment.
    4. To assess safety and tolerability of simvastatin add-on to NTZ or OCR treatment.
    5. To explore differences in efficacy on the described measures between subgroups based on demographics, MS subtype or disease modifying therapy.
    1. Onderzoeken van de effectiviteit van add-on hoge dosis simvastatine in bovengenoemde populatie op regionale grijze en witte stof volumes.
    2. De potentie van serum NfL als voorspeller van behandelrespons en ziekte progressie exploreren.
    3. Het effect op klinische, andere beeldvormende en patiënt gerapporteerde uitkomstmaten van ziekte progressie van add-on hoge dosis simvastatine behandeling onderzoeken.
    4. De veiligheid en verdraagbaarheid van add-on simvastatine bij natalizumab of ocrelizumab behandeling.
    5. Bekijken van de verschillen in effectiviteit op de beschreven uitkomstmaten en veiligheid tussen subgroepen op basis van demografische gegevens, MS subtype en immunomodulerende behandeling.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Definite diagnosis of multiple sclerosis (MS) according to the revised McDonald 2017 criteria.
    2. Treatment with ocrelizumab or natalizumab for at least 6 months prior to inclusion.
    4. Age 18 to 65 years old.
    5. EDSS score 3.0 – 7.0 (inclusive).
    1. Definitieve diagnose van MS volgens de gereviseerde McDonald 2017 criteria.
    2. Behandeling met ocrelizumab of natalizumab voor ten minste 6 maanden voorafgaand aan inclusie.
    3. Leeftijd 18 tot 65 jaar.
    4. EDSS score 3.0 - 7.0 (inclusief).
    E.4Principal exclusion criteria
    1. MS relapse within 6 months of baseline visit, with or without treatment with steroids.
    2. Use of immunomodulation or -suppression other than ocrelizumab or natalizumab within the previous 6 months.
    3. Commencement of treatment with fampridine within 3 months of baseline visit.
    4. Concomitant use of lipid lowering drugs or use within 6 months before baseline visit.
    5. Concomitant use of potent CYP3A4 inhibitors.
    6. (History of) hypersensitivity, muscular toxicity or other adverse reaction due to statin or fibrate use.
    7. Any predisposing factor to rhabdomyolysis: renal impairment (creatinine clearance <70 mL/min), uncontrolled hypothyroidism, personal or familial history of hereditary muscular disorders, alcohol abuse (>14 standard drinks units per week).
    8. Baseline serum creatine kinase (CK) levels of >5 x ULN (confirmed by second measurement within 5-7 days), or at least 3-fold increase from baseline with associated muscle symptoms.
    9. Active liver disease or unexplained persistent elevations of serum transaminases 3 x ULN.
    1. MS exacerbatie doorgemaakt in 6 maanden voor baseline visit, met of zonder behandeling met steroïden.
    2. Gebruik van andere immuunmodulerende of -suppressieve middelen dan ocrelizumab of natalizumab in de afgelopen 6 maanden.
    3. Start van behandeling met fampridine in 3 maanden voor baseline visit.
    4. Gelijktijdig gebruik van cholesterolverlagende middelen of gebruik in 6 maanden voor baseline visit.
    5. Gelijktijdig gebruik van potente CYP3A4 remmers.
    6. (Voorgeschiedenis van) overgevoeligheid, spier toxiciteit of andere ongewenste reactie door statine of fibraat gebruik.
    7. Eén of meer factoren die risico op rhabdomyolyse verhogen: nierinsufficiëntie (creatinine klaring <70 mL/min), hypohtyreoïdie die niet onder controle is, erfelijke spieraandoening bij patiënt of in diens familie, alcohol misbruik (>14 eenheden per week).
    8. Baseline serum creatine kinase (CK) levels >5 x ULN (bevestigd door tweede meting binnen 5-7 dagen), or ten minste 3 maal gestegen vanaf baseline met geassocieerde spiersymptomen.
    9. Actieve leveraandoening of onverklaarde persistente verhoging van serum transaminases van > 3 x ULN.
    E.5 End points
    E.5.1Primary end point(s)
    The change in whole brain atrophy rate, comparing rates during 6-month run-in period to 18-month treatment period.
    De verandering in hersenatrofie snelheid, waarbij de snelheid tijdens een run-in periode van 6 maanden vergeleken wordt met een behandelperiode van 18 maanden.
    E.5.1.1Timepoint(s) of evaluation of this end point
    - Baseline (month 0)
    - End of 6-month run-in period (month 6)
    - After 6 month of simvastatin treatment (month 12)
    - End of study (month 24)
    - Baseline (maand 0)
    - Einde van run-in periode van 6 maanden (maand 6)
    - Na 6 maanden simvastatine behandeling (maand 12)
    - Einde van de studie (maand 24)
    E.5.2Secondary end point(s)
    Secondary outcome measures include clinical outcome measures (neurological exam, arm- and walking functions, cognitive functions), biochemical outcome measures (sNfL, multi-parameter analysis of peripheral blood mononuclear cells (PBMC) and serum cholesterol), other imaging outcome measures (regional white and gray matter atrophy rate, functional connectivity on brain MRI, OCT), patient-reported outcome measures (questionnaires on the impact of MS on arm function, walking function, neuropsychological status and quality of life) and safety and tolerability (incidence of (serious) adverse events, CK levels).
    De secundaire uitkomstmaten betreffen klinische uitkomstmaten (neurologisch onderzoek, arm- en loopfuncties, cognitieve functies), biochemische uitkomstmaten (sNfL, multi-parameter analyse van mononucleaire cellen in perifeer bloed (PBMC) en serum cholesterol), andere beeldvorming (regionale hersenatrofie snelheden, functionele connectiviteit op MRI, OCT), patiënt-gerapporteerde uitkomstmaten (vragenlijsten over impact van MS op armfunctie, loopfunctie, neuropsychologische status en kwaliteit van leven) en veiligheid en verdraagbaarheid (incidentie van (serious) adverse events, CK levels)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Clinical testing (EDSS, MSFC, BICAMS, 6MWTEC), OCT and questionnaires are performed at baseline, month 6, month 12 and month 24. Biochemical measures including serum NfL are measured at baseline, month 6, month 7 and every 3 months between month 9 and 24. Adverse events survey is collected at baseline, month 6, month 7, every 3 months between month 9 and 24.
    Klinische testen (EDSS, MSFC, BICAMS, 6MWTEC), OCT en vragenlijsten worden afgenomen op baseline, maand 6, maand 12 en maand 24. Biochemische eindpunten inclusief serum NfL worden gemeten op baseline, maand 6, maand 7 en elke 3 maanden tussen maand 9 en 24. Een adverse events vragenlijst wordt verzameld bij baseline, maand 6, maand 7 en elke 3 maanden tussen maand 9 en 24.
    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 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.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 Yes
    E.8.1.7.1Other trial design description
    Run-in versus behandeling
    Run-in versus treatment
    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 No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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 months6
    E.8.9.1In the Member State concerned days
    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: 100
    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 state100
    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)
    None
    Geen
    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 Decision2020-04-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-03-24
    P. End of Trial
    P.End of Trial StatusOngoing
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