Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:
  • interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   42567   clinical trials with a EudraCT protocol, of which   7008   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).


    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) .

    Clinical Trials marked as "Trial now transitioned" were transitioned to the Clinical Trial Regulation 536/2014 and can be further followed in the Clinical Trial Information System  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Print Download

    Summary
    EudraCT Number:2019-002470-32
    Sponsor's Protocol Code Number:APHP190131
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2022-01-27
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2019-002470-32
    A.3Full title of the trial
    NEw Clinical End-points in patients with primary Sjögren's Syndrome (pSS): an Interventional Trial based on stratifYing patients
    Nuovi end-points clinici in pazienti con sindrome di Sjögren primaria (pSS): uno studio interventistico basato sulla stratificazione dei pazienti.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Nuovi end-points clinici in pazienti con sindrome di Sjögren primaria (pSS): uno studio interventistico basato sulla stratificazione dei pazienti.
    NEw Clinical End-points in patients with primary Sjögren's Syndrome (pSS): an Interventional Trial based on stratifYing patients
    A.3.2Name or abbreviated title of the trial where available
    NECESSITY
    NECESSITY
    A.4.1Sponsor's protocol code numberAPHP190131
    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 SponsorASSITANCE PUBLIQUE DES HOPITAUX DE PARIS
    B.1.3.4CountryFrance
    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 supportInnovative Medicines Initiative 2
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationASSISTANCE PUBLIQUE - HOPITAUX DE PARIS ( AP-HP)
    B.5.2Functional name of contact pointProject manager
    B.5.3 Address:
    B.5.3.1Street AddressDRCI Hôpital St Louis, 1 av claude vellefaux
    B.5.3.2Town/ cityParigi
    B.5.3.3Post code75010
    B.5.3.4CountryFrance
    B.5.4Telephone number+330140275724
    B.5.5Fax number+330144841701
    B.5.6E-mailisabelle.vivaldo@aphp.fr
    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 Arava
    D.2.1.1.2Name of the Marketing Authorisation holderSanofi Winthrop Industrie
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    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 nameLeflunomide
    D.3.2Product code [Leflunomide]
    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 INNLEFLUNOMIDE
    D.3.9.1CAS number 75706-12-6
    D.3.9.2Current sponsor codeLEFLUNOMIDE
    D.3.9.4EV Substance CodeSUB08424MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 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 Mycophenolate mofetil TEVA
    D.2.1.1.2Name of the Marketing Authorisation holderTEVA
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    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 namemycophenolate mofetil
    D.3.2Product code [mycophenolate mofetil]
    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 INNMICOFENOLATO MOFETILE
    D.3.9.2Current sponsor codemicofenolato mofetile
    D.3.9.4EV Substance CodeSUB03360MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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: 3
    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 PLAQUENIL
    D.2.1.1.2Name of the Marketing Authorisation holderSanofi
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    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 nameHydroxychloroquine
    D.3.2Product code [Hydroxychloroquine]
    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 INNHYDROXYCHLOROQUINE SULFATE
    D.3.9.1CAS number 747-36-4
    D.3.9.2Current sponsor code747-36-4
    D.3.9.4EV Substance CodeSUB02587MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 3
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Primary Sjögren's syndrome (pSS)
    sindrome di Sjögren primaria (pSS)
    E.1.1.1Medical condition in easily understood language
    Primary Sjögren's syndrome (pSS)
    sindrome di Sjögren primaria (pSS)
    E.1.1.2Therapeutic area Body processes [G] - Immune system processes [G12]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10040767
    E.1.2Term Sjogren's syndrome
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue disorders
    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 efficacy of each active treatment combination (hydroxychloroquine + leflunomide and hydroxychloroquine + mycophenolate mofetil) based on proportion of responder patients according to preliminary STAR at week 24.
    Valutare l’efficacia di ciascuna combinazione di trattamento attivo (idrossiclorochina e leflunomide o idrossiclorochina e micofenolato mofetile) per il trattamento di pSS. in funzione alla percentuale di pazienti responder alla settimana 24, come definito in base all’endpoint STAR preliminare.
    E.2.2Secondary objectives of the trial
    Cohort 1 and 2 together:
    To evaluate efficacy of each active treatment combination based on proportion of responder patients according to preliminary STAR at w24
    Cohorts 1 and 2 separately:
    To evaluate efficacy of each active treatment combination at w12 and 36 based on proportion of responder patients according to preliminary STAR
    To evaluate efficacy of each active treatment combination at w12, 24 and 36 based on change in ESSPRI.
    To evaluate efficacy of each active treatment combination at w12, 24 and 36 based on change in ESSDAI/clinESSDAI
    To assess discriminant capacity of STAR (preliminary STAR and alter opt) relative to ESSDAI (clinESSDAI)/ESSPRI to detect changes at w24 and 36
    To evaluate effect of each active treatment combination on - glandular function at w12, 24, 36
    To evaluate anxiety and depression, health-related QoL at w12, 24 and 36
    To evaluate utility of the PEPSS WebApp in collecting symptoms on a daily basis over 24 weeks
    Entrambe Coorti 1 e 2: Valutare efficacia di ciascuna combinaz. di trattam. in funzione alla percent. di pazienti responder alla sett. 24, secondo lo STAR prelim.
    Coorti 1 e 2 separat., valutare: efficacia di ogni combinaz. di trattam. attivo attraverso la percent. di paz. rispond. in base a endpoint STAR prelim., a 12 e 36 sett.; efficacia di ogni combinaz. di trattam. attivo sulla base del cambiam. del punteggio ESSPRI, a 12, 24 e 36 sett.; efficacia di ogni combinaz. di trattam. attivo sulla base del cambiam. nel punteggio di ESSDAI/clinESSDAI, a 12, 24 e 36 sett.; Testare capacità discriminante di STAR nel rilevare i cambiam. rispetto a ESSDAI (clinESSDAI)/ESSPRI, a 24 e 36 sett.; effetto di ogni combinaz. di trattam. attivo sulla funz.tà ghiandol. a 12, 24 e 36 sett.; effetto di ogni combinaz. di trattam. attivo su ansia, depressione e qualità della vita correlata alla salute, a 12, 24, e 36 sett.; utilità WebApp PEPSS nella raccolta giorn. dei sintomi, in un periodo di 24 sett.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives

    Other types of substudies
    Specify title, date and version of each substudy with relative objectives: Cohorts 1 and 2 separately:
    • To evaluate the efficacy of each active treatment combination at week 12, 24 and 36 based on proportion of responder patients according to STAR alternate options 1,2,3,4,5,7, 8, 9, 10, 12, 13, 14, 15, 16 and 17.
    • To evaluate the efficacy of each active treatment combination at week 12, 24 and 36 based on change in STAR alternate options 11, 18 and 19.
    • To evaluate the efficacy of each active treatment combination at week 12, 24 and 36 based on change in PhGA, PatGA and oral dryness VAS and ocular dryness VAS.
    • To evaluate the efficacy of each active treatment combination at week 24 and 36 based on change in SSSD.
    • To evaluate the effect of each active treatment combination based on patient's opinion and physician evaluation of change.
    • To evaluate the effect of each active treatment combination on sexual quality of life and ocular surface disease index at week 12, 24 and 36.
    • To assess and compare the discriminant capacity of meibography and non-invasive tear break-up time techniques to detect changes.
    • To assess the discriminant capacity of the novel ultrasound scoring system to detect changes.
    • To assess the utility of the biosensors to assess fatigue and detect changes.
    • To evaluate the change of several biomarkers from baseline after treatment.
    • To evaluate if the baseline level of several biomarkers is predictive of the treatment response.
    • To evaluate the change of salivary gland histologic abnormalities after treatment.

    Altre tipologie di sottostudi
    specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: Coorti 1 e 2 separatamente:
    • Per valutare l'efficacia di ciascuna combinazione di trattamento attivo alla settimana 12, 24 e 36 in base alla proporzione di pazienti responder secondo
    STAR opzioni alternative 1,2,3,4,5,7, 8, 9, 10, 12, 13, 14, 15, 16 e 17.
    • Per valutare l'efficacia di ciascuna combinazione di trattamento attivo alla settimana 12, 24 e 36 in base al cambiamento delle opzioni alternative STAR 11, 18 e 19.
    • Per valutare l'efficacia di ciascuna combinazione di trattamento attivo alla settimana 12, 24 e 36 in base al cambiamento di PhGA, PatGA e VAS sulla secchezza orale e VAS sulla secchezza oculare .
    • Valutare l'efficacia di ciascuna combinazione di trattamento attivo a settimana 24 e 36 in base al cambiamento in SSSD.
    • Per valutare l'effetto di ciascuna combinazione di trattamento attivo sulla base del parere del paziente e la valutazione del cambiamento da parte del medico.
    • Per valutare l'effetto di ogni combinazione di trattamento attivo della qualità della vita nell' ambito della sessualità e indice di malattia della superficie oculare alle settimane 12, 24 e 36.
    • Valutare e confrontare la capacità discriminante della meibografia e tecniche non invasive del tempo di rottura lacrimale per rilevarne i cambiamenti.
    • Valutare la capacità discriminante del nuovo sistema punteggio ecografico per rilevare i cambiamenti.
    • Valutare l'utilità dei biosensori per valutare la fatica e rilevare i cambiamenti.
    • Valutare il cambiamento di diversi biomarcatori rispetto al basale dopo trattamento.
    • Valutare se il livello basale di diversi biomarcatori è predittivo della risposta al trattamento.
    • Per valutare il cambiamento delle anomalie istologiche delle ghiandole salivari dopo il trattamento.
    E.3Principal inclusion criteria
    Cohort 1
    - Having given written informed consent prior to undertaking any studyrelated procedures.
    - Patients with pSS according to ACR/EULAR 2016 criteria or AECG 2002 criteria
    - With a high level of symptoms (ESSPRI = 5) and low systemic disease activity (ESSDAI < 5).
    - Negative pregnancy test (serum at screening)
    - Use highly reliable contraception (as defined in section 6.3) during research treatment from the screening and for two years after stopping treatment.
    Cohort 2
    - Having given written informed consent prior to undertaking any studyrelated procedures.
    - Patients with pSS according to ACR/EULAR 2016 criteria or AECG 2002 criteria.
    - With moderate/high systemic disease activity, as defined by ESSDAI = 5.
    - Negative pregnancy test (serum at screening)
    - Use highly reliable contraception (as defined in section 6.3) during research treatment from the screening and for two years after stopping treatment.
    Coorte 1:
    • Consenso informato scritto prima di intraprendere qualunque procedura di studio;
    • Diagnosi di pSS definita secondo i criteri ACR/EULAR 2016 o secondo i criteri AECG 2002;
    • Livello di sintomi alto (ESSPRI = 5) bassa attività di malattia sistemica (ESSDAI < 5);
    • Test di gravidanza su siero negativo (effettuato allo screening);
    • Impiego del trattamento di metodi contraccettivi altamente efficaci, dallo screening fino a due anni dopo l’interruzione.
    Coorte 2:
    • Consenso informato scritto prima di intraprendere qualunque procedura di studio;
    • Diagnosi di pSS definita secondo i criteri ACR/EULAR 2016 o secondo i criteri AECG 2002;
    • Attività di malattia sistemica di livello moderato/alto, definita da ESSDAI = 5;
    • Test di gravidanza su siero negativo (effettuato allo screening);
    • Impiego di metodi contraccettivi altamente affidabili, dallo screening fino a due anni dopo l’interruzione del trattamento.
    E.4Principal exclusion criteria
    For both cohorts:
    - Age < 18 years
    - Pregnant or breastfeeding women or women wanted to conceive either during or within two years after the end of the treatment period
    - Women of childbearing potential not using highly effective methods of contraception (as defined in section 6.3)
    - Participation in another interventional trial
    - Contra-indication to HCQ: pre-existing retinopathy, hypersensitivity to HCQ or to any of the excipients of the specialty used
    - Contra-indication to MMF: hypersensitivity to mycophenolate mofetil, acid mycophenolic, mycophenolate sodium or to any of the excipients of the specialty used
    - Contra-indication tor LEF: hypersensitivity to the active substance, the main active metabolite teriflunomide or to any excipients of the specialty used.
    - Concomitant treatment with corticosteroids more than 10 mg/day of prednisone equivalent at screening or inclusion (randomisation)
    - Concomitant treatment with other immunomodulators including methotrexate, azathioprine, cyclophosphamide, cyclosporine and tacrolimus
    - Previous treatment with HCQ, LEF, MMF in the last 3 months
    - Previous treatment with rituximab, other B-cell targeted biologic therapy or cyclophosphamide in the last 6 months
    - Previous treatment with anti-TNF, abatacept, tocilizumab or belimumab or any other biologic in the setting of a past clinical trial in the last 3 months
    - Severe life-threatening systemic involvement requiring cyclophosphamide or high dose corticosteroids, or any drug considered as an exclusion criteria
    - Impairment of other severe immunodeficiency states
    - Patients with active malignancy or history of malignancy within the last 5 years except non-melanoma skin cancer
    - Patients with history of gastrointestinal tract ulceration, hemorrhage and perforation
    - Patients with history of cardiomyopathy
    - Patients with known hereditary deficiency of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) such as Lesch-Nyhan and Kelley-Seegmiller syndrome
    - Serious infection in the past month
    - Evidence of active tuberculosis infection
    - Active HCV (positive PCR)
    - Active HBV infection (positivity for HBS antigen, or positivity for anti-HBC antibody without any HBS antigen)
    - HIV infection (positive serology)
    - Positive SARS-Cov2 PCR (if vaccinated for COVID-19, no PCR is required; if history of COVID-19 infection, positive serology is sufficient)
    - Cytopenia defined as neutrophils < 1.0 G/L, lymphocytes < 0.5 G/L, Hb < 10 g/dl or platelets < 100 G/L
    - Moderate to severe renal insufficiency (GFR < 30 ml/min)
    - Severe hypogammaglobulinemia defined as gamma globulins or IgG < 5 g/l
    - Reduced hepatic function: AST or ALT > 2x ULN (re-testing is allowed, see section 5.10)
    - Prolonged ECG's corrected QT interval (>500 ms)
    - Known history of maculopathy
    - Patients will be informed of the risk of alcohol consumption and will be recommended to avoid alcohol during the entire study
    - Not affiliated to a social security regime (specific for France)
    Per entrambe le coorti:
    • Età < 18 anni;
    • Gravidanza o allattamento in corso, o donne che desiderano intraprendere una gravidanza durante lo studio o nei due anni che seguono la conclusione del trattamento;
    • Donne potenzialmente fertili che non impiegano metodi contraccettivi altamente efficaci;
    • Partecipazione ad un'altra sperimentazione clinica interventistica;
    • Controindicazioni all’uso di HCQ: retinopatie pre-esistenti, ipersensibilità a HCQ o a qualunque degli eccipienti contenuti nella specialità utilizzata;
    • Controindicazioni all’uso di MMF: ipersensibilità al micofenolato mofetile, acido micofenolico, sodio micofenolato o a qualunque eccipiente della specialità utilizzate;
    • Controindicazioni a LEF: ipersensibilità al principio attivo, al principale metabolita attivo teriflunomide o a qualunque eccipiente utilizzato nella specialità;
    • Terapia concomitante con corticosteroidi a dosi maggiori di 10 mg/die di prednisone-equivalente allo screening o all’inclusione (randomizzazione);
    • Terapia concomitanti con altri immunomodulanti incluso metotrexato, azatioprina, ciclofosfamide, ciclosporina e tacrolimus;
    • Precedente trattamento con HCQ, LEF, MMF negli ultimi 3 mesi;
    • Precedente trattamento con rituximab, altre terapie biologiche mirate alle cellule B o ciclofosfamide negli ultimi 6 mesi;
    • Precedente trattamento con anti-TNF, abatacept, tocilizumab o belimumab o qualunque altro farmaco biologico nell’ambito di studi clinici negli ultimi 3 mesi;
    • Condizioni sistemiche gravi a rischio di sopravvivenza che richiedono ciclofosfamide, o alti dosaggi di corticosteroidi o qualunque altro farmaco considerato come criterio di esclusione;
    • Compromissione dovuta ad altre gravi condizioni di immunodeficienza;
    • Pazienti con patologie maligne attive o anamnesi positiva per malignità negli ultimi 5 anni, ad eccezione del tumore cutaneo non melanomatoso;
    • Pazienti con storia di ulcera gastrointestinale, emorragia e perforazione;
    • Pazienti con storia di cardiomiopatia;
    • Pazienti con deficienza ereditaria di ipoxantina-guanina fosforibosil-transferasi (HGPRT) come la sindrome Lesch-Nyhan e Kelley-Seegmiller;
    • Infezioni serie nell’ultimo mese;
    • Evidenza di infezione tubercolare attiva;
    • Infezione attiva da HCV (confermata da analisi PCR);
    • Infezione attiva da HBV (sierologia positiva per antigeni HBS o positività per anticorpi anti-HBC in assenza di antigeni HBS);
    • Infezione da HIV (sierologia positiva);
    • Infezione da SARS-Cov2 confermata da tecnica PCR (in caso di vaccinazione per COVID-19 non è richiesta analisi PCR; in caso di precedente infezione di COVID-19 è sufficiente sierologia positiva);
    • Citopenia definita da valori di neutrofili < 1.0 x 109/L, linfociti < 0.5 x x 109/L, Emoglobina < 10 g/dl o piastrine < 100 x 109/L;
    • Insufficienza renale da moderata a grave (GFR < 30 ml/min);
    • Grave ipogammoglobulinemia definita come valore di gammaglobuline o Immunoglobuline G < 5 g/l;
    • Ridotta funzionalità epatica, valore di AST o ALT superiore a due volte il limite superiore di normalità (in questo caso è consentita la ripetizione del test);
    • Prolungato intervallo QT corretto (> 500ms);
    • Pazienti con storia nota di maculopatia;
    • I pazienti saranno informati del rischio del consumo di alcol e sarà loro raccomandato di evitare il consumo di alcol durante l’intero studio;
    • Pazienti senza assistenza sanitaria (criterio specifico per la Francia).
    E.5 End points
    E.5.1Primary end point(s)
    Each cohort is analysed separately

    • Cohort 1: Proportion of patients achieving a response according to preliminary STAR at week 24 between each active treatment arm and placebo arm.

    • Cohort 2: Proportion of patients achieving a response according to preliminary STAR at week 24 between each active treatment arm and placebo arm.
    End-points primari:

    Coorte 1: Percentuale di pazienti per ogni braccio di trattamento attivo e per il braccio di placebo, che in base a STAR preliminare ottiene una risposta a 24 settimane.

    Coorte 2: Percentuale di pazienti per ogni braccio di trattamento attivo e nel braccio di placebo, che in base a STAR ottiene una risposta a 24 settimane.
    E.5.1.1Timepoint(s) of evaluation of this end point
    24 weeks
    24 settimane
    E.5.2Secondary end point(s)
    Cohorts 1 and 2 together
    • Cohort 1 and 2: Proportion of patients achieving a response according to preliminary STAR at week 24 between each active treatment arm and placebo arm.

    Cohorts 1 and 2 (the two cohorts will be analysed separately):
    • Proportion of patients achieving a response according to preliminary STAR from baseline at week 12 and 36 between each active treatment
    arm and placebo arm.
    • Change in ESSPRI from baseline at week 12, 24 and 36 between each active treatment arm and placebo arm. The difference of ESSPRI score at week 12, 24 and 36 (adjusted for baseline value) will be also compared between each active treatment arm and placebo arm.
    • Proportion of patients achieving a response in ESSPRI (defined as a decrease of ESSPRI score of = 1 (or = 15%)) from baseline at week 12,
    24 and 36 between each active treatment arm and placebo arm.
    • Change in ESSDAI/clinESSDAI from baseline at week 12, 24 and 36 between each active treatment arm and placebo arm. The difference of ESSDAI/clinESSDAI score at week 12, 24 and 36 (adjusted for baseline value) will be also compared between each active treatment arm and placebo arm.
    Cohort 1: This analysis will be performed only if the number of patients with ESSDAI/clinESSDAI > 0 is sufficient.
    • Proportion of patients achieving a response in ESSDAI/clinESSDAI (defined as improvement of ESSDAI/clinESSDAI = 3 points) from baseline at week 12, 24 and 36 between each active treatment arm and placebo arm.
    • Discriminant capacity of STAR (preliminary STAR and alternate options) relative to ESSDAI (clinESSDAI)/ESSPRI at week 24 and 36 to detect changes in the placebo arm versus in each active treatment arm in each cohort and globally
    • Change in unstimulated whole salivary flow from baseline at week 12, 24 and 36 between each active treatment arm and placebo arm.
    • Change in Schirmer's score from baseline at week 12, 24 and 36 between each active treatment arm and placebo arm.
    • Change in Tear Break-up time score from baseline at week 24 and 36 between each active treatment arm and placebo arm.
    • Change in Ocular Staining Score from baseline at week 24 and 36 between each active treatment arm and placebo arm.
    • Change in score of HADS questionnaire from baseline at week 12, 24 and 36 between each active treatment arm and placebo arm.
    • Change in score of EQ-5D-5L questionnaire from baseline at week 12, 24 and 36 between each active treatment arm and placebo arm.
    • Change in symptoms collected using the PEPSS WebApp from baseline to week 24 between each active treatment arm and placebo arm.
    Per entrambe le coorti 1 e 2:
    -Percentuale di pazienti per ogni braccio di trattamento attivo e per il braccio di placebo, che raggiunge una risposta in base a STAR preliminare a 24 settimane;

    Coorti 1 e 2 (ogni coorte sarà analizzata singolarmente):
    - Percentuale di pazienti per ogni braccio di trattamento attivo e per il braccio di placebo, che in base a STAR preliminare ottiene una risposta, rispetto al baseline, a 12 e 36 settimane;
    - Cambiamenti nel punteggio di ESSPRI tra ogni braccio di trattamento attivo e il braccio di placebo rilevati, rispetto al baseline, a 12, 24, e 36 settimane. Sarà inoltre confrontata la differenza del punteggio ESSPRI ottenuto a 12, 24, e 36 settimane (corretto per i valori del baseline) tra i singoli bracci di trattamento attivo e il braccio di placebo;
    -Percentuale di pazienti per ogni gruppo di trattamento attivo e per il braccio di placebo, che raggiungono una risposta in termini di ESSPRI (definito come riduzione = 1 (o = 15%) del punteggio ESSPRI), rispetto al baseline, a 12, 24, e 36 settimane;
    -Cambiamenti nel punteggio di ESSDAI/clinESSDAI tra ogni braccio di trattamento attivo e il braccio di placebo rilevati, rispetto al baseline, a 12, 24, e 36 settimane. Sarà inoltre confrontata la differenza del punteggio ESSDAI/clinESSDAI ottenuto a 12, 24, e 36 settimane (corretto per i valori della baseline) tra i singoli bracci di trattamento attivo e il braccio di placebo;

    Coorte 1: questa analisi sarà effettuata esclusivamente se presente un numero sufficiente di pazienti aventi ESSDAI/clinESSDAI >0.

    - Percentuale di pazienti per ogni braccio di trattamento attivo e per il braccio di placebo, che raggiunge una risposta in termini di ESSDAI/clinESSDAI (definito come aumento =3 nel punteggio ESSDAI/clinESSDAI) rispetto al baseline, a 12, 24, e 36 settimane;
    -Capacità discriminante di STAR (STAR preliminare e opzioni alternative) nel rilevare i cambiamenti rispetto a ESSDAI (clinESSDAI)/ESSPRI tra il braccio di placebo ed i singoli bracci di trattamento attivo, sia per singola coorte che in totale, a 24 e 36 settimane;
    -Cambiamenti nel flusso salivare non stimolato, tra ogni braccio di trattamento attivo e il braccio di placebo, dal baseline a 12, 24 e 36 settimane;
    -Cambiamenti nel punteggio relativo al test di Schirmer’s, tra ogni braccio di trattamento attivo e il braccio di placebo, dal baseline a 12, 24 e 36 settimane;
    -Cambiamenti del tempo di rottura del film lacrimale, tra ogni braccio di trattamento attivo e il braccio di placebo, dal baseline a 24 e 36 settimane;
    -Cambiamenti del punteggio relativo allo “staining” oculare, tra ogni braccio di trattamento attivo e il braccio di placebo, dal baseline a 24, e 36 settimane;
    -Cambiamenti del punteggio relativo al questionario HADS (Hospital Anxiety and Depression Scale), tra ogni braccio di trattamento attivo e il braccio di placebo, dal baseline a 12, 24 e 36 settimane;
    -Cambiamenti nel punteggio relativo al questionario EQ-5D-5L, tra ogni braccio di trattamento attivo e il braccio di placebo, dal baseline a 12, 24, e 36 settimane;
    -Cambiamenti dei sintomi registrati tramite la WebApp PEPSS, tra ogni braccio di trattamento attivo e il braccio di placebo, dal baseline a 24 settimane;
    E.5.2.1Timepoint(s) of evaluation of this end point
    6 months
    6 mesi
    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 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
    exploratory
    esploratoria
    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 Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    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 Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA34
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    France
    Greece
    Italy
    Netherlands
    Norway
    Spain
    Sweden
    United Kingdom
    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
    LPLV
    LPLV
    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 months10
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months10
    E.8.9.2In all countries concerned by the trial 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: 250
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 50
    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 state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 270
    F.4.2.2In the whole clinical trial 300
    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
    nessuno
    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 Decision2021-07-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-10-05
    P. End of Trial
    P.End of Trial StatusOngoing
    For support, visit the EMA Service Desk , log in using your EMA account and open a ticket specifying "EU CTR" in your request.
    If you do not have an account, please visit the EMA Account management page page click on "Create an EMA account" and follow the instructions.
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2022 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA