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    Summary
    EudraCT Number:2014-002796-28
    Sponsor's Protocol Code Number:CEASESTIFFNESS
    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:2015-04-23
    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 number2014-002796-28
    A.3Full title of the trial
    The Clinical Efficacy And Subclinical Effects on arterial STIFFNESS of bosentan therapy added to usual care in patients with systemic sclerosis with digital ulcers.
    De klinische effectiviteit en subklinische effecten op de vaatstijfheid van bosentan therapie toegevoegd aan de standaard behandeling bij patiënten met systemische sclerose met digitale ulcera.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Does therapy with bosentan tablets have positive effects on the stiffness of the vessels in patients with scleroderma who have ulcers of the fingers of toes?
    Heeft de behandeling met bosentan tabletten possitieve effecten op de stijfheid van de bloedvaten bij patienten met sclerodermie met zweertjes aan de vingers of tenen?
    A.3.2Name or abbreviated title of the trial where available
    CEASE STIFFNESS
    CEASE STIFFNESS
    A.4.1Sponsor's protocol code numberCEASESTIFFNESS
    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 Medical Center Groningen (UMCG)
    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 (UMCG)
    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 pointDJ Mulder
    B.5.3 Address:
    B.5.3.1Street AddressHanzeplein 1
    B.5.3.2Town/ cityGroningen
    B.5.3.3Post code9713GZ
    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 Yes
    D.2.1.1.1Trade name Tracleer
    D.2.1.1.2Name of the Marketing Authorisation holderActelion
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/03/139
    D.3 Description of the IMP
    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 INNbosentan
    D.3.9.1CAS number 157212-55-0
    D.3.9.2Current sponsor codeACT-050088
    D.3.9.3Other descriptive nameBOSENTAN MONOHYDRATE
    D.3.9.4EV Substance CodeSUB22249
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number125 to 250
    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
    Systemic sclerosis (SSc) is characterized by skin fibrosis and visceral disease, mainly of the lungs, kidneys and the heart, accompanied by microvascular damage ultimately leading to digital ischemia. Digital ischaemia, digital ulceration (DU) or amputation are well-known manifestations of SSc. Still over 50% of the SSc patients suffer from DU. Despite effort and treatment modalities that have emerged, DU remain an important complication in SSc, even in those with mild disease.
    Systemische sclerose (SSc) wordt gekarakteriseerd door huidfibrose en schade aan verschillende organen, met name de longen, nieren en het hart zijn aangedaan, gepaard met microvasculaire schade wat uiteindelijk leidt tot digitale ischemie. Digitale ischemie, digitale ulcera (DU) en amputatie zijn bekende manifestaties van SSc. Meer dan 50% van de patiënten hebben DU. Ondanks de nieuwe behandelingen blijven DU een belangrijke complicatie in SSc, ook in patiënten met milde ziekte.
    E.1.1.1Medical condition in easily understood language
    Systemic sclerosis (SSc) is a disease wich leads to skinfibrosis and internal organ disease. Over 50% of the SSc patients has ulceration at the fingertips, leading to disability and pain.
    Systemische sclerose is een ziekte wat kan leiden tot huidverlittekening en orgaanschade. Meer dan 50% van de patiënten heeft zweertjes aan de vingers, wat leidt tot functionele beperking en pijn.
    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
    To investigate whether bosentan added to usual care improves arterial stiffness after 3 months as measured as the pulse wave velocity (PWV) of the medium and large arteries corrected for blood pressure changes in patients with SSc with digital ulcers.
    Onderzoeken of bosentan toegevoegd aan de standaard behandeling de arteriële vaatstijfheid na 3 maanden, gemeten als de polsgolfsnelheid van de middelgrote en grote arteriën gecorrigeerd voor de bloeddruk, verbetert bij patiënten met SSc met digitale ulcera.
    E.2.2Secondary objectives of the trial
    To investigate whether bosentan added to usual care improves arterial stiffness after 1 year as measured as the pulse wave velocity (PWV) of the medium and large arteries corrected for blood pressure changes in patients with SSc with digital ulcers and also the intima media thickness, the nailfold capillaries (assesed by nailfold microscopy) after 3 months and 1 year. Also to investigate whether bosentan added to usual care improves clinical outcomes such as the modified Rodnan skin score and the quality of life assesed by the Scleroderma Health Assessment Questionnaire (SHAQ), EuroQol EQ-5D, and SF-36.
    Onderzoeken of bosentan toegevoegd aan de standaard behandeling de arteriële vaatstijfheid na 1 jaar, gemeten als de polsgolfsnelheid van de middelgrote en grote arteriën gecorrigeerd voor de bloeddruk, verbetert bij patiënten met SSc met digitale ulcera en of de intima media dikte en nagelriem capillairen (beoordeeld door de nagelriem capillairmicroscopie) verbeteren na 3 maanden en 1 jaar. Daarnaast onderzoeken of bosentan toegevoegd aan de standaard behandeling klinische uitkomstmaten verbeterd zoals de modified Rodnan skin score en of het de kwaliteit van leven verbeterd, beoordeeld door vragenlijsten ('Scleroderma Health Assessment Questionnaire' (SHAQ), EuroQol EQ-5D, en SF-36).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • 18 years or older
    • Systemic sclerosis based on the 2013 ACR/EULAR criteria
    • Raynaud’s phenomenon (RP)
    • A history of digital ulcer disease
    • Assessable Pulse Wave Velocity (PWV) measurement at baseline
    • Written informed consent
    • 18 jaar of ouder
    • Systemische sclerose volgens de 2013 ACR/EULAR criteria
    • Fenomeen van Raynaud (RP)
    • Een voorgeschiedenis van digitale ulcers
    • Goed te beoordelen polsgolf snelheid (Pulse Wave Velocity)
    • Getekend informed consent
    E.4Principal exclusion criteria
    • Hypersensitivity to the active substance or to any of the excipients
    • Moderate to severe hepatic impairment, i.e., Child-Pugh class B or C
    • Baseline values of liver aminotransferases, i.e., aspartate
    aminotransferases (AST) and/or alanine aminotransferases (ALT), greater
    than 3 times the upper limit of normal
    • Concomitant use of cyclosporine A
    • Pregnancy
    • Women of child-bearing potential who are not using reliable methods of
    contraception
    • Significant peripheral vascular disease as the sole consequence of
    atherosclerotic disease due to for example diabetes, dyslipidemia,
    systemic hypertension, coagulopathy
    • Overgevoeligheid voor een bestanddeel van de medicatie
    • Matig tot ernstige leverstoornissen, Child-Pugh class B or C
    • Baseline waarden van lever aminotransferasen, zoals aspartaat
    aminotransferasen (AST) en/of alanine aminotransferasen (ALT), grroter
    dan 3 maal de bovengrens van normaal
    • Gelijktijden gebruik van cyclosporine A
    • Zwangerschap
    • Vrouw waarbij zwangerschap mogelijk is, die geen betrouwbare
    anticonceptie gebruikt
    • Significante perifeer vaatlijden als gevolg van atherosclerose of
    bijvoorbeeld diabetes, dyslipidemie, systemische hypertensie of
    coangulopathie.
    E.5 End points
    E.5.1Primary end point(s)
    Mean of right and left carotid-femoral arterial (i.e. aortic) Pulse Wave Velocity (cfPWV)
    Gemiddelde van rechter en linker carotis-femoraal arteriële (aorta) polsgolf snelheid (PWV).
    E.5.1.1Timepoint(s) of evaluation of this end point
    At baseline, 3 months and 1 year.
    Bij het starten van de studie, na 3 maanden en na 1 jaar.
    E.5.2Secondary end point(s)
    • Right and left carotid-brachial and carotid-radial arterial PWV (cbPWV
    and crPWV)
    • Local PWV of the right and left radial (rPWV), brachial (bPWV),
    femoral (fPWV), and common carotid artery (cPWV)
    • Mean intima media thickness (IMT) of right and left radial, brachial,
    femoral, and common carotid artery
    • Nail-fold Capillary Microscopy and derived indices: Microangiopathy
    Evolution Score (MES), Capillaroscopic Skin Ulcer Risk Index (CSURI) and
    Prognostic Index for Digital Laesions (PILD)
    • Blood flow in the hands, and in different regions of the hands (region
    of interest (ROI) 1, ROI 2 and ROI 3), as measured by Laser Doppler
    Perfusion Imaging (LDPI) at standardised ambient hand temperature.
    • Skin Autofluorescence
    • Mean number of new DUs per and time to healing of the cardinal ulcer
    • Urine albumin/creatinine ratio (ACR)
    • Plasma NT-proBNP and uric acid
    • Serum levels of matrix metalloproteinases (MMP 3 and MMP 9), and
    tissue inhibitors of metalloproteinases (TIMP)
    • Systolic, diastolic, and mean arterial blood pressure of the brachial
    artery
    • Modified Rodnan Skin Score (mRSS)
    • inclusiez
    • Rechter en linker carotis-brachialis en carotis-radialis arteriële PWV
    (cbPWV en crPWV)
    • Lokale PWV van de rechter en linker radialis (rPWV), brachialis
    (bPWV), femoralis (fPWV) en de carotis arterie (cPWV).
    • Gemiddelde intima media dikte (IMT) van de rechter en linker radialis,
    brachialis, femoralis and carotis arterie.
    • Nagelriem capillairmicroscopie en afgeleide indexen: microangiopathie
    evolutie score (MES), "Capillaroscopic Skin Ulcer Risk Index" (CSURI) en
    prognostische index voor digitale afwijkingen (PILD)
    • Blood flow in de handen en in verschillende regios van de handen
    ("region of interest" (ROI) 1, ROI 2 and ROI 3), gemten door "Laser
    Doppler Perfusion Imaging" (LDPI) bij een gestandaardiseerde
    temperatuur.
    • Huid auto fluorescentie
    • Gemiddeld aantal van nieuwe DUs en de tijd die het duurt voor deze
    genezen is
    • Urine albumine/creatinine ratio (ACR)
    • Plasma NT-proBNP en urinezuur
    • Serum levels van matrix metalloproteinasen (MMP 3 en MMP 9), en
    "tissue inhibitors of metalloproteinases" (TIMP)
    • Systolische, diastolische, en gemiddelde arteriële bloeddruk van de a.
    brachialis
    • "Modified Rodnan Skin Score" (mRSS)
    • Sclerodermie Vragenlijst Dagelijks Functioneren, EuroQol EQ-5D en
    SF-36
    E.5.2.1Timepoint(s) of evaluation of this end point
    At baseline, 3 months and 1 year.
    Bij het starten van de studie, na 3 maanden en na 1 jaar.
    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 No
    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) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    De standaard behandeling, zonder het te onderzoeken product.
    The standard treatment, without the IMP.
    E.8.2.4Number of treatment arms in the trial2
    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 years2
    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: 40
    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 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 state40
    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)
    Standard treament and if wanted and/or considered necessary by treating physician the IMP.
    Standaard behandeling wordt vervolgd zoals gebruikelijk, daarnaast kan de patiënt als hij/zij dat wil en/of het nodig geacht wordt door de behandelend arts het te onderzoeken product (blijven) krijgen.
    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 Decision2016-04-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-04-13
    P. End of Trial
    P.End of Trial StatusOngoing
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