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    The EU Clinical Trials Register currently displays   41231   clinical trials with a EudraCT protocol, of which   6758   are clinical trials conducted with subjects less than 18 years old.
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    Phase 1 trials conducted solely in adults and that are not part of an agreed PIP are not public in the EU CTR (refer to European Guidance 2008/C 168/02   Art. 3 par. 2 and   Commission Guideline 2012/C 302/03,   Art. 5) .
     
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    Summary
    EudraCT Number:2019-004718-32
    Sponsor's Protocol Code Number:NL72607.041.20
    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:2020-10-09
    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 number2019-004718-32
    A.3Full title of the trial
    Upfront autologous hematopoietic stem cell transplantation versus immunosuppressive medication in early diffuse cutaneous systemic sclerosis: an international multicentre, open-label, randomized controlled trial
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Stem cell transplantation in diffuse cutaneous systemic sclerosis: upfront therapy or rescue therapy after failure of immunosuppressants?
    A.4.1Sponsor's protocol code numberNL72607.041.20
    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 SponsorUMC Utrecht
    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 supportZonMW
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUMC Utrecht
    B.5.2Functional name of contact pointprincipal investigator
    B.5.3 Address:
    B.5.3.1Street AddressHeidelberglaan 100
    B.5.3.2Town/ cityUtrecht
    B.5.3.3Post code3584 CX
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31887557357
    B.5.6E-mailj.m.vanlaar@umcutrecht.nl
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleComparator
    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.3.4Pharmaceutical form Powder for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    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 RoleComparator
    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.2.1.1.1Trade name Mycophenolate mofetil
    D.2.1.1.2Name of the Marketing Authorisation holderTEVA Pharma
    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.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    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
    Diffuse cutaneous systemic sclerosis according to the ACR/EULAR criteria
    E.1.1.1Medical condition in easily understood language
    Systemic sclerosis
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    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
    To determine the optimal treatment strategy in early dcSSc: the effect of HSCT as upfront therapy compared with that of immunosuppressive medication in early dcSSc, with respect to survival and prevention of major organ failure (referred to as ‘event-free survival’ which is considered as primary endpoint), safety and the impact on skin thickening, visceral involvement, functional status, and quality of life.
    E.2.2Secondary objectives of the trial
    To evaluate (in both treatment arms) whether disease activity correlates with immunological parameters, including immunopathology of skin, immune reconstitution, and autoantibodies. We will also determine the cost-effectiveness of HSCT as first line treatment versus usual care and try to identify factors associated with response to treatment
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Biomarker sub-study
    E.3Principal inclusion criteria
    1. Age between 18 and 65 years.
    2. Fulfilling the 2013 ACR-EULAR classification criteria
    3. Disease duration ≤ 2 years (from onset of first non-Raynaud’s symptoms) and
    - mRSS ≥ 15 (diffuse skin pattern) and/or
    - clinically significant organ involvement as defined by either:
    a) respiratory involvement
    b) renal involvement
    c) cardiac involvement
    E.4Principal exclusion criteria
    A potential subject who meets any of the following criteria will be excluded from participation in this study:
    1. Pregnancy or unwillingness to use adequate contraception during study
    2. Concomitant severe disease (respiratory, renal, cardiac, liver failure, psychiatric disorders including active drug or alcohol abuse, concurrent neoplasms or myelodysplasis, bone marrow insufficiency, uncontrolled hypertension, uncontrolled acute or chronic infection, including HIV, HTLV-1,2 positivity, ZUBROD-ECOG-WHO Performance Status Scale > 2
    3. Previous treatments with immunosuppressants > 6 months including mycophenolate mofetil, methotrexate, azathioprine, rituximab, tocilizumab, glucocorticosteroids.
    4. Previous treatments with TLI, TBI or alkylating agents including cyclophosphamide.
    5. Significant exposure to bleomycin, tainted rapeseed oil, vinyl chloride, trichlorethylene or silica;
    6. eosinophilic myalgia syndrome; eosinophilic fasciitis.
    7. Poor compliance of the patient as assessed by the referring physicians.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is event-free survival. Event-free survival is defined as the time in days from
    the day of randomisation until the occurrence of death due to any cause or the development of
    persistent major organ failure (heart, lung, kidney) defined as follows:
    • Heart: left ventricular ejection fraction < 30% by cardiac MR (or cardiac echo)
    • Lungs: respiratory failure = resting arterial oxygen tension (PaO2) < 8 kPa (< 60 mmHg) and/or resting arterial carbon dioxide tension (PaCO2) > 6.7 kPa (> 50 mmHg) without oxygen supply
    • Kidney: need for renal replacement therapy

    Note 1. When major organ failure has occurred, its persistence is to be confirmed by
    repeated evaluation after 3 months.

    Note 2. Cardiac MR is considered the gold standard for assessment of LVEF.
    LVEF measurements by cardiac echo (instead of cardiac MR) will be accepted when baseline and follow-up evaluations have been performed by the same experienced echocardiologist.
    E.5.1.1Timepoint(s) of evaluation of this end point
    3, 6, 9, 12, 15, 18, 21, 24 months after treatment
    E.5.2Secondary end point(s)
    - Progression-free survival, defined as the time in days since the day of randomisation until any of the following relative changes from baseline has been documented:
    • death,
    • ≥ 10% drop in (F)VC predicted and/or ≥ 15% drop in DLCO predicted,
    • ≥ 15% drop in LVEF by echo or cardiac MR,
    • ≥ 15% drop in body weight,
    • ≥ 30% drop in creatinine clearance,
    • ≥ 30% increase in skin score,
    • ≥ 0.5 increase in SHAQ.
    - Treatment related mortality is defined as any death during the study period following randomisation
    that cannot be attributed to progression of the disease according to the consensus opinion of the DSMB.
    - Treatment toxicity will be assessed using WHO toxicity parameters (adverse events =/> grade 3) in consecutive 3-month periods following randomisation until two years follow-up.
    - The area under the curve (AUC) of the CRISS over time, measuring the ‘predicted probability of being im-proved’ over 2 years.(22) This AUC is calculated based on 4 repeated measures (6, 12, 18 and 24 months) with back translation to the original scale between 0 and 1.
    - Change over years follow-up of the following parameters:
    • modified Rodnan skin score by independent assessor (appendix G)
    • Pulmonary involvement = diffusion capacity for carbon monoxide (DLCO and DLCO/VA), (forced)vital capacity ((F)VC), total lung capacity (TLC), residual volume (RV), mean pulmonary artery pressure by cardiac echo (or right heart catheterization), lung density measurement by thoracic CT
    • Renal involvement = urine portion: creatinin/ protein ratio
    Myocardial involvement= left ventricular function as measured by cardiac MR (at baseline and 12 months), ECG and cardiac echo (annually) and semiquantitative measurement of cardiac involvement with the cardiac score (based on the presence or absence of left axis deviation on ECG and moderate or large pericardial effusion on echo).(23)
    Quality-of-life (EuroQol (EQ-5D-5L)) (appendix H)
    Customized version (focussing on the important cost-drivers) of the iMCQ and iPCQ (appendix I)
    SHAQ incl visual analogue scales (VAS) for scleroderma-specific symptoms (appendix J)
    Gastrointestinal symptom scale (UCL-GIT 2.0) (appendix K)
    Sexual functioning (IIEF-5 and BMSFI (in men) and Sexual Function Questionnaire (SFQ-28)) (appendix L)
    E.5.2.1Timepoint(s) of evaluation of this end point
    3, 6, 9, 12, 15, 18, 21, 24, 36, 48, 60 months after treatment
    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.7.1.3.1Other 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 Yes
    E.8.1.1Randomised Yes
    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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    autologous stem cell transplantation
    E.8.2.4Number of treatment arms in the trial2
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA6
    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 years7
    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 years7
    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: 120
    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 state60
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 60
    F.4.2.2In the whole clinical trial 120
    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
    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 Decision2020-10-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-08-18
    P. End of Trial
    P.End of Trial StatusOngoing
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