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    Summary
    EudraCT Number:2018-001719-65
    Sponsor's Protocol Code Number:CALC-SSc
    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:2018-07-09
    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 number2018-001719-65
    A.3Full title of the trial
    CALCification as an early marker of vasculopathy and organ involvement in Systemic Sclerosis
    CALC-SSc study
    Calcificatie als vroege marker van vaat-en orgaanschade bij systemische sclerose (SSc)̓
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    CALCification as an early marker of vasculopathy and organ involvement in Systemic Sclerosis
    CALC-SSc study
    Calcificatie als vroege marker van vaat-en orgaanschade bij systemische sclerose (SSc)̓
    A.3.2Name or abbreviated title of the trial where available
    CALC-SSc study
    CALC-SSc studie
    A.4.1Sponsor's protocol code numberCALC-SSc
    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 SponsorUniversity Medial Center Groningen
    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 supportUniversity Medical Center Groningen
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Medical Center Groningen
    B.5.2Functional name of contact pointD.J. Mulder
    B.5.3 Address:
    B.5.3.1Street AddressHanzeplein 1
    B.5.3.2Town/ cityGroningen
    B.5.3.3Post code9713 GZ
    B.5.3.4CountryNetherlands
    B.5.6E-maild.j.mulder@umcg.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 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.3.1Product nameSodium fluoride 18F
    D.3.2Product code EMA/CHMP/212874/2015
    D.3.4Pharmaceutical form 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 Yes
    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
    Systemic sclerosis (SSc) is a rare progressive autoimmune disease hallmarked by severe vasculopathy. Patients are prone to enhanced calcification of skin and the vasculature. Active calcifications may not only occur in the skin of patients with clinically overt calcinosis cutis, but also in SSc patients without. Since calcification is strongly associated with local inflammation, it may very well occur in internal organs and serve as an early proxy for long-term SSc-related complications.
    Scleroderma (SSc) is een zeldzame, progressieve auto-immuun ziekte welke gekenmerkt wordt door vasculopathie. Patiënten zijn gevoelig voor verkalking van de huid . Actieve kalkafzettingen kan zich niet alleen in de huid van patiënten met klinisch overduidelijke calcinosis cutis manifesteren, maar ook in SSc patiënten zonder. Verkalking is sterk geassocieerd met lokale ontsteking, en kan daarom optreden in inwendige organen en fungeren als een vroege voorspeller van SSc-gerelateerde complicaties.
    E.1.1.1Medical condition in easily understood language
    Systemic sclerosis is a rare progressive disease hallmarked by vasculopathy. Raynaud phenomenon is usually the first presenting symptom, after which more skin en organ involvement evolves.
    Sclerodermie is een zeldzame, progressieve ziekte gekenmerkt door vasculopathie. Het Raynaud fenomeen is meestal het eerste symptoom, waarna meer onomkeerbare schade aan organen en de huid onstaat.
    E.1.1.2Therapeutic area Diseases [C] - Skin and Connective Tissue Diseases [C17]
    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
    1. To assess serum calcification propensity (T50) in SSc patients compared with healthy age and gender-matched controls;
    1. om de hoeveelheid serum T50 in SSc patiënten te vergelijken met gezonde leeftijd en geslacht gematchte controles;
    E.2.2Secondary objectives of the trial
    2. To assess serum T50 in SSc patients with overt calcinosis cutis as compared to age and gender-matched SSc patients without;
    3. To assess other serum markers of the calcification process in SSc patients compared with healthy age and gender-matched controls as compared to age and gender-matched SSc patients without;
    4. To assess serum T50 and other serum markers of the calcification process compared with established markers of the underlying disease process;
    5. To assess serum T50 compared with non-invasive markers of micro- and macrovasculopathy in patients with SSc;
    6. To assess serum T50 compared with SSc-related skin and internal organ complications;
    7. To study associations with expression of markers involved in the calcification process in skin biopsies by immunohistochemistry;
    8. To assess whether AGEs/HMGB1-RAGE interactions lead to increased IFN-1 signature and profibrotic and osteogenic differentiation of fibroblasts isolated from skin biopsies;
    2. de hoeveelheid serum T50 in SSc patiënten met overduidelijke calcinosis cutis vergelijken met leeftijd en geslacht gematchte SSc patiënten zonder overduidelijke calcinosis cutis
    3. andere serummarkers van het proces van verkalking in SSc patiënten vergelijken met gezonde leeftijd en geslacht gematchte controles en leeftijd en geslacht gematchte SSc patiënten zonder overduidelijke calcinosis cutis
    4. serum T50 en andere serummarkers van het proces van verkalking vergelijken met bekende markers van het onderliggende ziekteproces;
    5. serum T50 vergelijken met niet-invasieve merkers van micro- en macrovasculopathie in patiënten met SSc
    6. serum T50 vergelijken met SSc gerelateerde huid en inwendige organen complicaties
    7. expressie van markers die betrokken zijn bij het proces van verkalking in huid nagaan via immunohistochemie
    8. nagaan of AGEs/HMGB1-RAGE interacties leiden tot verhoogde IFN-1 en profibrotische/osteogene differentiatie van fibroblasten geïsoleerd uit huidbiopten
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    The feasibility of imaging the calcification process using 18F-NaF PET/CT scans in patients with SSc.

    Date: 16-4-2018, Version: 1

    Objectives:
    1. Degree of active large arterial vessel calcifications and in skin, intestines, kidneys and lungs;
    2. Degree of stable large vessel calcifications.
    De haalbaarheid van de beeldvorming van het verkalkingsproces met behulp van 18F-NaF PET/CT scans bij patiënten met SSc.

    Datum: 16-4-2018, Versie: 1

    Doelen:
    1. mate van actieve kalkafzettingen in arteriën en de huid, darmen, nieren en longen;
    2. mate van stabiele kalkafzettingen.
    E.3Principal inclusion criteria
    SSc patients:
    In order to be eligible to participate in this study as an SSc patient, a subject must meet all of the following criteria:
    • 18-80 years
    • Formal diagnosis of Systemic Sclerosis, as determined by a total of ≥9 from adding the maximum weight (score) in each of the following categories (2013 ACR/EULAR criteria):
    o Skin thickening of the fingers of both hands extending proximal to the metacarpophalangeal joints (sufficient criterion) (9 points)
    o Skin thickening of the fingers (only count the higher score)
     Puffy fingers (2 points)
     Sclerodactyly of the fingers (distal to the metacarpophalangeal joints but proximal to the proximal interphalangeal joints) (4 points)
    o Fingertip lesions (only count the higher score)
     Digital tip ulcers (2 points)
     Fingertip pitting scars (3 points)
    o Telangiectasia (2 points)
    o Abnormal nailfold capillaries (2 points)
    o Pulmonary involvement (maximum score is 2)
     Pulmonary arterial hypertension (2 points)
     Interstitial lung disease (2 points)
    o Raynaud’s phenomenon (3 points)
    o SSc-related autoantibodies (maximum score is 3)
     Anticentromere (3 points)
     anti–topoisomerase I [anti–Scl-70] (3 points)
     anti–RNA polymerase III (3 points)
    • Written informed consent

    Controls:
    In order to be eligible to participate in this study as a patient with primary Raynaud’s phenomenon, a subject must meet all of the following criteria:
    • 18-80 years
    • Negatieve antinuclear antibodies (ANA)
    • Normal nailfold capillairies
    • No underlying disease
    • Written informed consent

    Healthy controls:
    In order to be eligible to participate in this study as a healthy control, a subject must meet all of the following criteria:
    • 18-80 years
    • No apparent underlying chronic disease
    • No signs and symptoms suggesting Raynaud phenomenon or other vascular disease
    • Written informed consent
    SSc patiënten:
    • 18-80 jaar
    • Formele diagnose van systeemsclerose, zoals bepaald door een totaalscore van ≥9 aan de hand van de volgende categorieën (criteria van de ACR/EULAR 2013):
    o verdikking van de huid van de vingers van beide handen met proximale uitbreiding van de metacarpophalangeal gewrichten (voldoende criterium) (9 punten)
    o verdikking van de huid van de vingers (alleen hoogste score meetellen)
     - Gezwollen vingers (2 punten)
     - Sclerodactylie van de vingers (distaal van de metacarpophalangeale gewrichten maar proximaal van de proximale interfalangeale gewrichten) (4 punten)
    o vingertop laesies (alleen hooste score meetellen)
     - Digitale vingertop zweren (2 punten)
     - Vingertop littekens (3 punten)
    o Telangiectasia (2 punten)
    o abnormale nagelbed haarvaten (2 punten)
    o pulmonaire betrokkenheid (maximale score is 2)
     - Pulmonale arteriële hypertensie (2 punten)
     - Interstitiele longziekte (2 punten)
    o Raynaud-fenomeen (3 punten)
    o SSc-gerelateerde autoantilichamen (maximale score is 3)
     Anti-centromeren (3 punten)
     anti-topoisomerase I [anti-Scl-70] (3 punten)
     anti-RNA polymerase III (3 punten)
    • Schriftelijke toestemming

    Controles met Raynaud:
    • 18-80 jaar
    • Negatieve antinucleaire antilichamen (ANA)
    • Normale nagelbed haarvaten
    • Geen onderliggende ziekte
    • Schriftelijke toestemming

    Gezonde controles:
    • 18-80 jaar
    • Geen onderliggende chronische ziekte
    • Geen tekenen of symptomen die Raynaud fenomeen of andere vasculaire ziekten suggereren
    • Schriftelijke toestemming
    E.4Principal exclusion criteria
    A potential subject who meets any of the following criteria will be excluded from participation in this study:
    • Women who are currently pregnant, planning to become pregnant, breastfeeding women, or women with child bearing potential not using appropriate contraceptive measures
    • Patients who are mentally incompetent and cannot sign a Patient Informed Consent or are unwilling to sign a Patient Informed Consent
    • Vascular event in the preceding 3 months (33)
    • Chemotherapy in the preceding 3 months (33)
    • Inflammation of unknown origin, sepsis, or vasculitis (34)

    The next criteria will also be used for the substudy concerning 18F-NaF PET/CT:
    • Current active bone malignancy or in the previous 6 months (35)
    • Fractures or metastases within the evaluated bone regions, as well as metallic implants (33)
    • Disorders affecting bone metabolism, e.g. hyperparathyroidism, Paget’s disease (33)
    • Patients who have claustrophobia (16)
    • Prior or present bisphosphonate therapy (33)
    • Prior or present calcium or vitamin D therapy
    • Vrouw die op dit moment zwanger is, vrouwen die borstvoeding geven of vrouwen met een kinderwens die geen anticonceptie gebruiken
    • Patiënten die geestelijk onbekwaam en geen toestemmingformulier kunnen tekenen of niet bereid zijn deze te ondertekenen
    • Vasculaire aandoening in de voorafgaande 3 maanden
    • Chemotherapie in de voorafgaande 3 maanden
    • Ontsteking van onbekende oorsprong, sepsis of vasculitis

    De volgende criteria zullen ook worden gebruikt voor de sub-studie betreffende 18F-NaF PET/CT:
    • Huidige actieve bot maligniteit of in de voorafgaande 6 maanden
    • Fracturen of metastasen binnen de geëvalueerde bot regio's, alsmede de aanwezigheid van metalen implantaten
    • Aandoeningen die het bot metabolisme beïnvloeden, bijvoorbeeld hypoparathyreoïdie, de ziekte van Paget
    • Patiënten met claustrofobie
    • Voorgaande of huidige bisfosfonaat therapie
    • Voorgaande of huidige calcium of vitamine D therapie
    E.5 End points
    E.5.1Primary end point(s)
    1. Degree of serum T50;
    1. de hoeveelheid serum T50.
    E.5.1.1Timepoint(s) of evaluation of this end point
    At baseline
    Eenmalig bij aanvang studie
    E.5.2Secondary end point(s)
    2. Degree of other serum markers of the calcification process: calcium; phosphorus; parathormone; fetuin-A; FGF23; αKlotho;
    3. Degree of blood markers involved in inflammation, calcification and endothelial dysfunction: plasma AGEs (CML, pentosidine and MG-H1); HMGB1; carbonyl markers; skin AF as marker of dermal AGE accumulation (biomarkers of the AGE-RAGE axis); ET-1; C-reactive protein, erythrocyte sedimentation rate (ESR), IL-6, whole blood IFN- I signature (biomarkers of endothelial activation and inflammation); VEGF, IL-8, angiogenic T cells, TIE2 positive monocytes (biomarkers of angiogenesis);
    4. Degree of vascularopathy measured by: capillary microscopy; arterial stiffness measured by PWV; digital artery involvement assessed with ultrasound;
    5. Degree of cardiac involvement by cardiac ultrasound, pulmonary involvement by conventional lung function (FVC, DLCO), and subsequent HRCT upon indication, renal involvement by kidney function (24-hours creatinine clearance, proteinuria, and glomerular erythrocyturia) and gastro-intestinal involvement by conventional oesophageal motility scan;
    6. Degree of markers involved in the calcification process as well as biomarkers of progression to SSc in skin biopsies: degree of fibrosis (TGFβ, collagen); αKlotho; FGF23; myxovirus resistance gene A (MxA) which is a marker for IFNα, TLR 4 and TLR 8;
    7. Degree of fibroblasts sensitivity to calcification and proinflammatory mechanisms by: CML-modified-bovine serum albumin (BSA); HMGB1, RAGE, and TGFβ.
    2. de hoeveelheid van andere serummarkers in het verkalkingsproces: calcium; fosfaat; parathormoon; fetuin-A; FGF23; ΑKlotho;
    3. de hoeveelheid van bloedmarkers die betrokken zijn bij ontsteking, verkalking en endotheel disfunctie: plasma AGEs (CML, pentosidine en MG-H1); HMGB1; carbonyl markers; huid AF; ET-1; C - reactief proteïne, bezinkingssnelheid (ESR), IL-6, IFN - I; VEGF, IL-8, angiogenic T cellen, TIE2 positieve monocyten;
    4. de mate van vasculopathie gemeten door: capillair microscopie; arteriële vaatstijfheid gemeten met PWV; betrokkenheid van de slagaders in de vingers beoordeeld met echografie;
    5. de graad van cardiale betrokkenheid door cardiale echografie, pulmonale betrokkenheid door conventionele longfunctie (FVC, DLCO) en daaropvolgende HRCT op indicatie, nier betrokkenheid door nierfunctie (24-uurs creatinineklaring, proteïnurie, en glomerulaire erythrocyturie) en gastro-intestinale betrokkenheid door conventionele oesofageale motiliteit scan;
    6. mate van markers die betrokken zijn bij het verkalkingsproces evenals biomarkers voor de progressie naar SSc in huid biopsieën: mate van fibrose (TGFβ, collageen); ΑKlotho; FGF23; Myxovirus resistentie gen A (MxA);
    7. mate van gevoeligheid van fibroblasten voor verkalking en pro-inflammatoire mechanismen door: CML-gewijzigd-boviene serumalbumine (BSA); HMGB1, RAGE en TGFβ.
    E.5.2.1Timepoint(s) of evaluation of this end point
    At baseline
    Eenmalig bij aanvang studie
    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 No
    E.6.5Efficacy No
    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 Yes
    E.6.13.1Other scope of the trial description
    Pathofysiologie
    Pathofysiologie
    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 No
    E.8.1.1Randomised No
    E.8.1.2Open No
    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 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 No
    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 years4
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    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 Yes
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state120
    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 Decision2018-07-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-12-10
    P. End of Trial
    P.End of Trial StatusOngoing
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