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    Summary
    EudraCT Number:2016-001121-14
    Sponsor's Protocol Code Number:CL010_168
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2018-06-22
    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 ConcernedFrance - ANSM
    A.2EudraCT number2016-001121-14
    A.3Full title of the trial
    A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to Evaluate the Safety and Efficacy of CCX168 (Avacopan) in Patients with Anti-Neutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis Treated Concomitantly with Rituximab or Cyclophosphamide/Azathioprine
    Étude de phase 3 randomisée, en double aveugle, contrôlée contre placebo, évaluant la sécurité et l’efficacité de CCX168 (Avacopan) chez des sujets présentant une vascularite associée à des anticorps anti-cytoplasme des polynucléaires neutrophiles (ANCA) traités conjointement avec Rituximab ou Cyclophosphamide/Azathioprine
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Clinical Trial to Evaluate the Safety and Efficacy of CCX168 (Avacopan), a new drug for the treatment of Vasculitis of a certain type, called ANCA-Associated Vasculitis (AAV).
    Essai clinique évaluant la sécurité et l’efficacité du CCX168 (Avacopan), un nouveau médicament pour le traitement de vascularite d'un certain type appelé vascularite associée à des anticorps anti-cytoplasme des polynucléaires neutrophiles (ANCA)
    A.4.1Sponsor's protocol code numberCL010_168
    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 SponsorChemoCentryx, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportChemoCentryx, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationChemoCentryx, Inc.
    B.5.2Functional name of contact pointAntonia Potarca
    B.5.3 Address:
    B.5.3.1Street Address850 Maude Avenue
    B.5.3.2Town/ cityMountain View, CA
    B.5.3.3Post code94043
    B.5.3.4CountryUnited States
    B.5.4Telephone number+31 6 30892290
    B.5.5Fax number+1650-210-2910
    B.5.6E-mailapotarca@chemocentryx.com
    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 Yes
    D.2.5.1Orphan drug designation numberMPA - EMA/OD/149/14, GPA - EMA/OD/150/14
    D.3 Description of the IMP
    D.3.1Product nameAvacopan
    D.3.2Product code CCX168
    D.3.4Pharmaceutical form Capsule
    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 INNAvacopan
    D.3.9.1CAS number 1346623-17-3
    D.3.9.2Current sponsor codeCCX168
    D.3.9.3Other descriptive nameCCX168
    D.3.9.4EV Substance CodeSUB31899
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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 Prednison acis® 5 mg
    D.2.1.1.2Name of the Marketing Authorisation holderacis Arzneimittel GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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
    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 INNPednisone
    D.3.9.1CAS number 53-03-2
    D.3.9.3Other descriptive namePREDNISONE
    D.3.9.4EV Substance CodeSUB10020MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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: 3
    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 Prednison acis® 20 mg
    D.2.1.1.2Name of the Marketing Authorisation holderacis Arzneimittel GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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
    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 INNPednisone
    D.3.9.1CAS number 53-03-2
    D.3.9.3Other descriptive namePREDNISONE
    D.3.9.4EV Substance CodeSUB10020MIG
    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 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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule
    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 placeboCapsule
    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 placeboCapsule
    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
    Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis
    vascularite associée à des anticorps anti-cytoplasme des polynucléaires neutrophiles (ANCA)
    E.1.1.1Medical condition in easily understood language
    Vasculitis (a disorder that destroys blood vessels by inflammation) of a certain kind, called ANCA-associated vasculitis
    vascularite (un trouble qui détruit les vaisseaux sanguins par inflammation) d'un certain type appelé vascularite associée à des anticorps anti-cytoplasme des polynucléaires neutrophiles (ANCA)
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10072579
    E.1.2Term Granulomatosis with polyangiitis
    E.1.2System Organ Class 10047065 - Vascular disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10063344
    E.1.2Term Microscopic polyangiitis
    E.1.2System Organ Class 10047065 - Vascular disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10050894
    E.1.2Term Anti-neutrophil cytoplasmic antibody positive vasculitis
    E.1.2System Organ Class 10021428 - Immune system disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective is to evaluate the efficacy of CCX168 (avacopan) to induce and sustain remission in patients with active anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), when used in combination with cyclophosphamide followed by azathioprine, or in combination with rituximab
    L’objectif principal est d’évaluer l’efficacité du CCX168 (avacopan) en termes d’induction et de maintien d’une rémission chez les patients atteints de vascularite associée aux anticorps anti-cytoplasme des polynucléaires neutrophiles (ANCA) (VAA), lorsqu’il est associé au cyclophosphamide, puis à l’azathioprine, ou au rituximab
    E.2.2Secondary objectives of the trial
    1. Evaluation of the glucocorticoid-induced toxicity compared between test and control group
    2. Evaluation of rapidity of response compared between test and control group
    3. Evaluation of the safety compared between test and control group
    4. Assessment of health-related quality-of-life changes compared between test and control group
    5. Assessment of changes in parameters of renal disease compared between test and control group
    6. Assessment of changes in cumulative organ damage compared between test and control group
    7. Assessment of changes in markers of pharmacodynamics in plasma and urine compared between test and control group
    8. Evaluation of the pharmacokinetic profile of CCX168 in patients with AAV.
    1. Évaluation de la toxicité induite par les glucocorticoïdes entre le groupe test et le groupe contrôle
    2. Évaluation de la rapidité de la réponse dentre le groupe test et le groupe contrôle
    3. Évaluation de la sécurité du traitement entre le groupe test et le groupe contrôle
    4. Évaluation des changements en termes de qualité de vie liée à la santé entre le groupe test et le groupe contrôle
    5. Évaluation des changements relatifs aux paramètres de maladie rénale entre le groupe test et le groupe contrôle
    6. Évaluation des changements relatifs aux lésions cumulatives des organes entre le groupe test et le groupe contrôle
    7. Évaluation des changements des marqueurs pharmacodynamiques dans le plasma et les urines entre le groupe test et le groupe contrôle
    8. Évaluation du profil pharmacocinétique du CCX168 chez les patients atteints de VAA.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Clinical diagnosis of granulomatosis with polyangiitis (Wegener's) or microscopic polyangiitis, consistent with Chapel-Hill Consensus Conference definitions
    2. Aged at least 18 years, with newly-diagnosed or relapsed AAV where treatment with cyclophosphamide or rituximab is needed; where approved, adolescents (12-17 year old) may be enrolled
    3. Positive test for anti-PR3 or anti-MPO (current or historic) antibodies
    4. At least one major item, or at least 3 minor items, or at least the 2 renal items of proteinuria and hematuria in the BVAS
    5. Estimated glomerular filtration rate ≥15 mL/minute/1.73 m2 (using the MDRD method) at screening
    6. Willing and able to give written Informed Consent and to comply with the requirements of the study protocol; written Informed Consent should be obtained from the legal guardian in accordance with regional laws or regulations for patients 12 to 17 years of age
    7. Judged by the Investigator to be fit for the study, based on medical history, physical examination (including electrocardiogram [ECG]), and clinical laboratory assessments.
    1. Diagnostic clinique de granulomatose avec polyangéite (de Wegener) ou de polyangéite microscopique, correspondant aux définitions de la Chapel-Hill Consensus Conference (Jennette et al, 2013)
    2. Être âgé d’au moins 18 ans, et être atteint d’une VAA récemment diagnostiquée ou récidivante nécessitant un traitement par cyclophosphamide ou rituximab ; lorsque cela est autorisé, des adolescents (entre 12 et 17 ans) peuvent être recrutés
    3. Test positif aux anticorps anti-PR3 ou anti-MPO (actuellement ou par le passé)
    4. Présenter au moins un des éléments majeurs, au moins trois des éléments mineurs ou au moins deux des éléments rénaux de protéinurie et d’hématurie du BVAS
    5. Débit de filtration glomérulaire estimé ≥ 15 ml/min/1,73 m2 (selon la méthode MDRD) lors de la sélection
    6. Être disposé à signer le formulaire de consentement éclairé et à respecter les exigences du protocole de l’étude ; pour les patients entre 12 et 17 ans, le formulaire de consentement éclairé doit être signé par le tuteur légal conformément aux législations ou règlements locaux
    7. Être considéré par l’Investigateur comme étant apte à participer à l’étude, sur la base des antécédents médicaux, de l’examen physique (y compris l’électrocardiogramme [ECG]) et des analyses biologiques.
    E.4Principal exclusion criteria
    1. Pregnant or breast-feeding
    2. Alveolar hemorrhage requiring invasive pulmonary ventilation support anticipated to last beyond the screening period of the study
    3. Any other known multi-system autoimmune disease including eosinophilic granulomatosis with polyangiitis (Churg-Strauss), systemic lupus erythematosus, IgA vasculitis (Henoch-Schönlein), rheumatoid vasculitis, Sjögren's syndrome, anti-glomerular basement membrane disease, or cryoglobulinemic vasculitis
    4. Required dialysis or plasma exchange within 12 weeks prior to screening
    5. Have had a kidney transplant
    6. Received cyclophosphamide within 12 weeks prior to screening; if on azathioprine, mycophenolate mofetil, or methotrexate at the time of screening, these drugs must be withdrawn prior to receiving the cyclophosphamide or rituximab dose on Day 1
    7. Received intravenous glucocorticoids, >3000 mg methylprednisolone equivalent, within 4 weeks prior to screening
    8. Have been taking an oral daily dose of a glucocorticoid of more than 10 mg prednisone-equivalent for more than 6 weeks continuously prior to the screening visit
    9. Received rituximab or other B-cell antibody within 52 weeks of screening or 26 weeks provided B cell reconstitution has occurred (i.e., CD19 count > 0.01x109/L); received anti-TNF treatment, abatacept, alemtuzumab, IVIg, belimumab, tocilizumab, or eculizumab within 12 weeks prior to screening
    10. Currently taking a strong inducer of the cytochrome P450 3A4 (CYP3A4) enzyme, such as carbamazepine, phenobarbital, phenytoin, rifampin, or St. John’s wort
    11. Any of the following within 12 weeks prior to screening: symptomatic congestive heart failure requiring prescription medication, unstable angina (unless successfully treated with stent or bypass surgery), clinically significant cardiac arrhythmia, myocardial infarction or stroke
    12. History or presence of any form of cancer within the 5 years prior to screening, with the exception of excised basal cell or squamous cell carcinoma of the skin, or carcinoma in situ such as cervical or breast carcinoma in situ that has been excised or resected completely and is without evidence of local recurrence or metastasis
    13. Evidence of tuberculosis based on interferon γ release assay (IGRA), tuberculin purified protein derivative (PPD) skin test, or chest radiography (X rays or CT scan) done at screening or within 6 weeks prior to screening
    14. HBV, HCV, or HIV viral screening test showing evidence of active or prior viral infection done at screening or within 6 weeks prior to screening
    15. Received a live vaccine within 4 weeks prior to screening
    16. WBC count less than 3500/μL, or neutrophil count less than 1500/μL, or lymphocyte count less than 500/µL before start of dosing
    17. Evidence of hepatic disease: AST, ALT, alkaline phosphatase, or bilirubin > 3 times the upper limit of normal before start of dosing
    18. Clinically significant abnormal ECG during screening, e.g., QTcF greater than 450 msec
    19. Known hypersensitivity to CCX168 or inactive ingredients of the CCX168 capsules (including gelatin, polyethylene glycol, or Cremophor), cyclophosphamide or its metabolites (for patients scheduled to receive cyclophosphamide), or known Type I hypersensitivity or anaphylactic reactions to murine proteins, Chinese Hamster Ovary cell proteins, or to any component of rituximab (for patients scheduled to receive rituximab)
    20. For patients scheduled to receive cyclophosphamide treatment, urinary outflow obstruction, active infection (especially varicella zoster infection), or platelet count < 50,000/L before start of dosing
    21. Participated in any clinical study of an investigational product within 30 days prior to screening or within 5 half-lives after taking the last dose;
    22. Participated previously in a CCX168 study
    23. History or presence of any medical condition or disease which, in the opinion of the Investigator, may place the patient at unacceptable risk for study participation
    1. Être enceinte ou allaiter
    2. Hémorragie intra-alvéolaire nécessitant une ventilation invasive devant se prolonger au-delà de la période de sélection de l’étude
    3. Toute autre maladie auto-immune systémique connue, notamment granulomatose éosinophilique avec polyangéite (syndrome de Churg-Strauss), lupus érythémateux systémique, purpura rhumatoïde (maladie de Henoch-Schönlein), vascularite rhumatoïde, syndrome de Gougerot-Sjögren, maladie de la membrane basale glomérulaire ou vascularite cryoglobulinémique
    4. Dialyse ou échange plasmatique nécessaire au cours des 12 semaines précédant la sélection
    5. Avoir subi une transplantation rénale
    6. Avoir reçu du cyclophosphamide au cours des 12 semaines précédant la sélection ; chez les patients recevant de l’azathioprine, du mycophénolate mofétil ou du méthotrexate au moment de la sélection, ces médicaments devront être arrêtés avant l’administration de la dose de cyclophosphamide ou de rituximab le Jour 1
    7. Avoir reçu par voie IV une dose de glucocorticoïdes équivalant à > 3000 mg de méthylprednisolone au cours des 4 semaines précédant la sélection
    8. Avoir pris par voie orale une dose journalière d’un glucocorticoïde équivalant à plus de 10 mg de prednisone pendant plus de 6 semaines consécutives avant la visite de sélection
    9. Avoir reçu du rituximab ou un autre anticorps anti-lymphocytes B au cours des 52 semaines précédant la sélection ou au cours des 26 semaines précédant la sélection à condition que les lymphocytes B se soient reconstitués (c-à-d., numération CD19 > 0,01 x 109/l) ; avoir reçu un traitement par anti-TNF, abatacept, alemtuzumab, IgIV, belimumab, tocilizumab ou éculizumab au cours des 12 semaines précédant la sélection ; les immunosuppresseurs non mentionnés ici devront faire l’objet d’une discussion avec le moniteur médical
    10. Prendre actuellement un puissant inducteur du cytochrome P450 3A4 (CYP3A4), tel que carbamazépine, phénobarbital, phénytoïne, rifampicine ou herbe de la saint-Jean
    11. Avoir présenté au moins l’un des troubles suivants au cours des 12 semaines précédant la sélection : insuffisance cardiaque congestive symptomatique nécessitant la prescription de médicaments, angor instable (sauf si traité par pose d’un stent ou pontage), arythmie cardiaque cliniquement significative, infarctus du myocarde ou AVC
    12. Antécédents ou présence de toute forme de cancer au cours des 5 années précédant la sélection, à l’exception des carcinomes basocellulaires ou épidermoïdes cutanés ayant fait l’objet d’une ablation, et des cancers in situ, tels que cancer in situ du col de l’utérus ou du sein, ayant fait l’objet d’une ablation ou d’une résection totale, et ne présentant aucun signe de récidive locale ou de métastase
    13. Tuberculose confirmée par un test de détection de l’interféron γ (IGRA), un test d’intradermoréaction à la tuberculine avec dérivé protéinique purifié (DPP) ou une radiographie des poumons réalisé(e) lors de la sélection ou au cours des 6 semaines précédant la sélection
    14. Test de dépistage des virus VHB, VHC ou VIH indiquant une infection virale active ou antérieure, réalisé lors de la sélection ou au cours des 6 semaines précédant la sélection
    15. Avoir reçu un vaccin vivant au cours des 4 semaines précédant la sélection
    16. Présenter un nombre de globules blancs inférieur à 3500/μl, un nombre de neutrophiles inférieur à 1500/μl ou un nombre de lymphocytes inférieur à 500/µl avant le début de l’administration
    17. Maladie hépatique confirmée : taux d’ASAT, ALAT, phosphatase alcaline ou bilirubine 3 fois supérieur à la limite supérieure de la normale avant le début de l’administration
    18. ECG présentant des anomalies cliniquement significatives pendant la sélection, par ex. intervalle QTcF supérieur à 450 ms
    19. Hypersensibilité connue au CCX168 ou aux excipients des gélules de CCX168 (notamment gélatine, polyéthylène glycol ou Cremophor), au cyclophosphamide ou à ses métabolites (pour les patients devant recevoir le cyclophosphamide), ou hypersensibilité de type I connue ou réactions anaphylactiques aux protéines murines, aux protéines des cellules CHO ou à tout autre composant du rituximab (pour les patients devant recevoir le rituximab)
    20. Pour les patients devant recevoir le traitement par cyclophosphamide, obstruction des voies urinaires, infection active (en particulier, infection au virus varicelle-zona) ou numération des plaquettes < 50 000/μl avant le début de l’administration
    21. Avoir participé à une étude clinique portant sur un produit expérimental au cours des 30 jours précédant la sélection ou des 5 demi-vies suivant la prise de la dernière dose
    22. Avoir déjà participé à une étude portant sur le CCX168
    23. Antécédents ou présence d’une maladie ou d’un trouble médical susceptible, selon l’Investigateur, de faire courir au patient un risque inacceptable s’il participe à l’étude.
    E.5 End points
    E.5.1Primary end point(s)
    1. The proportion of patients achieving disease remission at Week 26, defined as a BVAS of 0 and not taking glucocorticoids within 4 weeks prior to Week 26.
    2. The proportion of patients achieving sustained disease remission, defined as remission at Week 26 without relapse to Week 52 (BVAS of 0 and not taking glucocorticoids within 4 weeks prior to Week 52).
    1. Proportion de patients obtenant une rémission de la maladie à la Semaine 26, définie par un BVAS égal à 0 et une absence de prise de glucocorticoïdes au cours des 4 semaines précédant la Semaine 26.
    2. Proportion de patients obtenant une rémission prolongée, définie par une rémission à la Semaine 26 sans récidive jusqu’à la Semaine 52 (BVAS égal à 0 et absence de prise de glucocorticoïdes au cours des 4 semaines précédant la Semaine 52).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Both endpoints will be assessed after 52 weeks of treatment
    Ces 2 critères d’efficacité seront évalués après 52 semaines de traitement
    E.5.2Secondary end point(s)
    Secondary efficacy endpoints include:
    1. Glucocorticoid-induced toxicity as measured by change from baseline over the first 26 weeks in the glucocorticoid toxicity index;
    2. Early remission, defined as BVAS of 0 at Week 4;
    3. Change from baseline over 52 weeks in health-related quality-of-life as measured by the domains and component scores of the SF-36 v2 and EQ-5D-5L VAS and index;
    4. Proportion of patients and time to experiencing a relapse after previously achieving remission in the study; relapse is defined as occurrence of at least one major item in the BVAS, or three or more minor items in the BVAS, or one or two minor items in the BVAS recorded at two consecutive visits, after having achieved remission (BVAS = 0) in the study;
    5. In patients with renal disease at baseline (based in the BVAS renal component), the change in eGFR from baseline over 52 weeks;
    6. In patients with renal disease at baseline (based in the BVAS renal component), the percent change in UACR from baseline over 52 weeks;
    7. In patients with renal disease at baseline (based in the BVAS renal component), the percent change in urinary MCP-1:creatinine ratio from baseline over 52 weeks;
    8. Change in the VDI from baseline over 52 weeks.

    Safety endpoints, other than glucocorticoid-induced toxicity listed under the efficacy endpoints, include:
    1. Patient incidence of treatment-emergent serious adverse events, adverse events, and withdrawals due to adverse events;
    2. Change from baseline and shifts from baseline in all safety laboratory parameters;
    3. Change from baseline in vital signs, and
    4. Incidence of clinically significant ECG changes from baseline.

    PK endpoint:
    CCX168 (and metabolite) plasma concentration results will be used to calculate trough plasma concentrations (Cmin) over the course of the clinical trial.

    PD endpoints:
    The following PD endpoints may be assessed:
    1. Change and percent change from baseline in plasma biomarkers such as cystatin C, complement fragments, inflammatory chemokine and cytokine levels.
    2. Change and percent change from baseline in urine biomarkers such as renal injury and inflammation markers (e.g., KIM-1 and NGAL), soluble CD163, complement fragments, inflammatory chemokine and cytokine levels;
    3. Change from baseline in CBC count (especially WBCs, neutrophils, and lymphocytes) and lymphocyte subset counts including B cells, T cells, and natural killer cells;
    4. Change from baseline in blood cell gene expressions such as neutrophil functional status markers.

    The effect of polymorphism in genetic markers, as well as C5aR polymorphism may also be investigated.
    Les critères d’efficacité secondaires comprennent :
    1. Toxicité induite par les glucocorticoïdes déterminée par l’évolution du GTI (indice de toxicité des glucocorticoïdes) par rapport aux valeurs de référence, au cours des 26 premières semaines
    2. Rémission précoce, définie par un BVAS égal à 0 à la Semaine 4
    3. Évolution par rapport aux valeurs de référence de la qualité de vie liée à la santé déterminée par les domaines et scores de composante de l’échelle visuelle analogique (VAS) et de l’indice des questionnaires SF-36 v2 et EQ-5D-5L, sur 52 semaines
    4. Proportion de patients et délai de récidive ; on entend par récidive la survenue d’au moins un élément majeur du BVAS, d’au moins trois éléments mineurs du BVAS, ou d’un ou deux éléments mineurs du BVAS lors de deux visites consécutives, suite à l’obtention d’une rémission (BVAS = 0) pendant l’étude
    5. Chez les patients présentant une maladie rénale à l’inclusion (basée sur la composante rénale du BVAS), évolution du DGFe par rapport aux valeurs de référence sur 52 semaines
    6. Chez les patients présentant une maladie rénale à l’inclusion (basée sur la composante rénale du BVAS), évolution en pourcentage du RAC par rapport aux valeurs de référence sur 52 semaines
    7. Chez les patients présentant une maladie rénale à l’inclusion (basée sur la composante rénale du BVAS), évolution en pourcentage du rapport MCP-1/créatinine urinaire par rapport aux valeurs de référence sur 52 semaines
    8. Évolution du VDI par rapport aux valeurs de référence sur 52 semaines.
    E.5.2.1Timepoint(s) of evaluation of this end point
    various, refer to information in E.5.2
    divers, se referer aux informations en E.5.2
    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 Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    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) Yes
    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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    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 concerned13
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA106
    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 No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Austria
    Belgium
    Canada
    Czech Republic
    Denmark
    France
    Germany
    Hungary
    Ireland
    Italy
    Netherlands
    New Zealand
    Spain
    Sweden
    Switzerland
    United Kingdom
    United States
    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
    Dernière visite du dernier patient inclus
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    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 Yes
    F.1.1Number of subjects for this age range: 10
    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) Yes
    F.1.1.6.1Number of subjects for this age range: 10
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 240
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    adolescents
    adolescents
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 200
    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 - expected normal treatment of that condition
    aucun - Traitement normal de cette pathologie
    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 Decision2017-03-08
    N.Ethics Committee Opinion of the trial application
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion
    P. End of Trial
    P.End of Trial StatusCompleted
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