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    Summary
    EudraCT Number:2016-001121-14
    Sponsor's Protocol Code Number:CL010_168
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-01-20
    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 ConcernedSpain - AEMPS
    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
    Estudio de fase III randomizado, doble ciego y controlado con placebo para evaluar la seguridad y la eficacia de CCX168 (avacopán) en pacientes con vasculitis asociada a anticuerpos citoplásmicos antineutrofílicos (ANCA) tratados de forma concomitante con rituximab o ciclofosfamida/azatioprina
    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).
    Un ensayo clínico para evaluar la seguridad y la eficacia de CCX168 (Avacopan), un nuevo fármaco para el tratamiento de un determinado tipo de vasculitis, llamada Vasculitis Asociada a ANCA(AAV).
    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 organisationMedpace Spain S.L.
    B.5.2Functional name of contact pointMonica Bermejo
    B.5.3 Address:
    B.5.3.1Street Addressc/ Agustín de Foxa 29. 8ª Planta
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28036
    B.5.3.4CountrySpain
    B.5.4Telephone number+3491790056525454
    B.5.5Fax number+34900981853
    B.5.6E-mailSpain.Regulatory@medpace.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
    Vasculitis asociada a anticuerpos citoplásmicos antineutrofílicos (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
    Un cierto tipo de vasculitis (un trastorno que destruye los vasos sanguíneos por la inflamación) denominada vasculitis asociada a 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 19.1
    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 19.1
    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 19.1
    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
    El objetivo principal es evaluar la eficacia de CCX168 (avacopán) para inducir y mantener la remisión en pacientes con vasculitis asociada a anticuerpos citoplásmicos antineutrofílicos (ANCA) activa (VAA), cuando se usa en combinación con ciclofosfamida seguida de azatioprina, o en combinación con 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. Evaluación de la toxicidad inducida por glucocorticoides comparada entre los grupos de ensayo y de control.
    2. Evaluación de la rapidez de la respuesta comparada entre los grupos de ensayo y de control.
    3. Evaluación de la seguridad comparada entre los grupos de ensayo y de control.
    4. Evaluación de las variaciones en la calidad de vida relacionada con la salud comparada entre los grupos de ensayo y de control.
    5. Evaluación de las variaciones en los parámetros indicativos de nefropatía comparada entre los grupos de ensayo y de control.
    6. Evaluación de las variaciones en el daño orgánico acumulado comparada entre los grupos de ensayo y de control.
    7. Evaluación de las variaciones en los marcadores farmacodinámicos comparada entre los grupos de ensayo y de control
    8. Evaluación del perfil farmacocinético de CCX168 en pacientes con AAV.
    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. Diagnóstico clínico de granulomatosis con poliangitis (granulomatosis de Wegener) o poliangitis microscópica, según las definiciones de la Conferencia de Consenso de Chapel-Hill.
    2. Edad mínima de 18 años, con AAV de diagnóstico reciente o en recaída para la que se necesita tratamiento con ciclofosfamida o rituximab; cuando está aprobado, se podrán incluir adolescentes (de 12 a 17 años)
    3. Resultado positivo en la prueba de detección de anticuerpos anti-PR3 o anti-MPO (actual o histórica)
    4. Al menos un ítem principal, o como mínimo 3 ítems secundarios, o al menos dos ítems renales de proteinuria y hematuria en la escala BVAS.
    5. Filtración glomerular estimada ≥15 ml/min/1,73 m2 (según la ecuación del MDRD) en el screening.
    6. Querer y poder dar el consentimiento informado por escrito y cumplir con los requisitos del protocolo del estudio; para los pacientes de 12 a 17 años, el consentimiento informado por escrito debe obtenerse del tutor legal conforme a las leyes y reglamentos regionales.
    7. Estar en buen estado, según el investigador, para participar en el estudio, según la historia médica, la exploración física (incluido el electrocardiograma [ECG]) y las evaluaciones de los análisis clínicos.
    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. Embarazo o lactancia;
    2. Hemorragia alveolar que requiere soporte ventilatorio pulmonar invasivo, previsiblemente hasta después del periodo de screening del estudio
    3. Cualquier otra enfermedad autoinmunitaria con afectación multiorgánica, incluida granulomatosis eosinofílica con poliangitis (síndrome de Churg-Strauss), lupus eritematoso sistémico, vasculitis por IgA (púrpura de Henoch-Schönlein), vasculitis reumatoide, síndrome de Sjögren, enfermedad por anticuerpos contra la membrana basal glomerular o vasculitis crioglobulinémica
    4. Necesidad de diálisis o plasmaféresis en las 12 semanas previas al screening;
    5. Haber recibido un trasplante renal;
    6. Haber recibido ciclofosfamida en las 12 semanas previas al screening; si el paciente está en tratamiento con azatioprina, micofenolato mofetilo o metotrexato en el momento del screening, debe retirarse el tratamiento con estos fármacos antes de recibir la dosis de ciclofosfamida o rituximab el día 1
    7. Haber recibido glucocorticoides intravenosos, equivalente a >3000 mg de metilprednisolona, en las 4 semanas previas al screening
    8. Haber estado tomando una dosis oral diaria de un glucocorticoide (equivalente a más de 10 mg de prednisona) durante más de 6 semanas de forma ininterrumpida antes de la visita de screening
    9. Haber recibido rituximab u otro anticuerpo contra los linfocitos B en las 52 semanas anteriores al screening, siempre que se haya producido la reconstitución de los linfocitos B (es decir, cifra de CD19 >0,01 × 109/l); haber recibido tratamiento con anticuerpos anti-TNF, abatacept, alemtuzumab, IgIV, belimumab, tocilizumab o eculizumab en las 12 semanas previas al screening; los inmunosupresores no enumerados en esta lista deben comentarse con el monitor médico;
    10. En tratamiento actualmente con un inductor potente de la isoenzima 3A4 del citocromo P450 (CYP3A4), como carbamazepina, fenobarbital, fenitoína, rifampicina o hipérico (hierba de San Juan);
    11. Cualquiera de las siguientes enfermedades en las 12 semanas previas al screening: insuficiencia cardíaca congestiva sintomática que precisa medicación de venta con receta, angina inestable (salvo que se trate con éxito con la implantación de una endoprótesis vascular o con cirugía de derivación coronaria), arritmia cardíaca clínicamente significativa, infarto de miocardio o ictus;
    12. Antecedentes o presencia de cualquier forma de cáncer en los 5 años previos al screening, con la excepción de carcinoma cutáneo basocelular o espinocelular extirpado, o carcinoma localizado como carcinoma de cuello uterino o de mama preinvasor que se haya extirpado o resecado por completo y no haya signos de recidiva locorregional ni de metástasis;
    13. Signos de tuberculosis según la prueba de liberación de interferón γ (IGRA), la prueba de intradermorreacción de Mantoux (con derivado proteínico purificado, DPP) o una radiografía de tórax realizadas en el screening o en las 6 semanas anteriores;
    14. Pruebas de detección del VHB, del VBC o del VIH que muestren signos de infección vírica activa o previa, realizadas en el screening o en las 6 semanas previas;
    15. Haber recibido una vacuna atenuada en las 4 semanas previas al screening;
    16. Número de leucocitos menor de 3500/μl o recuento de neutrófilos inferior a 1500/μl o número de linfocitos menor de 500/μl antes del inicio de la administración;
    17. Signos de hepatopatía: AST, ALT, fosfatasa alcalina o bilirrubina >3 veces el límite superior de la normalidad antes del inicio de la administración
    18. ECG anómalo clínicamente significativo durante el screening (p. ej., intervalo QTcF mayor de 450 ms);
    19. Hipersensibilidad conocida a CCX168 o a los excipientes de las cápsulas de CCX168 (incluidos gelatina, polietilenglicol o Cremophor), la ciclofosfamida o sus metabolitos (para los pacientes en los que está programada la administración de ciclofosfamida) o hipersensibilidad de tipo I o reacciones anafilácticas a proteínas murinas, proteínas de células de ovario de hámster chino o a alguno de los componentes de rituximab (para los pacientes que deban recibir rituximab);
    20. Para los pacientes que está previsto que reciban tratamiento con ciclofosfamida, obstrucción urinaria, infección activa (especialmente infección por el virus de la varicela-zóster) o número de plaquetas <50 000/μl antes del inicio de la administración;
    21. Participación en otro ensayo clínico con un producto en fase de investigación en el plazo de 30 días antes del screening, o cinco semividas después de haber recibido la última dosis;
    22. Haber participado anteriormente en un estudio sobre CCX168; y
    23. Antecedentes o presencia de cualquier enfermedad o circunstancia médica que, en opinión del investigador, pueda poner al paciente en una situación de riesgo inaceptable si participa en el estudio.
    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. El porcentaje de pacientes que alcanzan la remisión de la enfermedad en la semana 26, definida como una puntuación BVAS de 0 y sin tomar glucocorticoides en las 4 semanas anteriores a la semana 26.
    2. El porcentaje de pacientes que alcanzan la remisión mantenida de la enfermedad, definida como remisión en la semana 26 sin recaída hasta la semana 52 (BVAS de 0 y sin tomar glucocorticoides en las 4 semanas anteriores a la semana 52).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Both endpoints will be assessed after 52 weeks of treatment
    Ambos criterios de valoración se evaluarán después de 52 semanas de tratamiento
    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.
    1. Toxicidad inducida por glucocorticoides, medida mediante el cambio respecto al periodo basal en el índice de toxicidad por glucocorticoides en las primeras 26 semanas;
    2. Remisión temprana, definida como una puntuación de la escala BVAS de 0 en la semana 4;
    3. Variación respecto al periodo basal durante 52 semanas en la calidad de vida relacionada con la salud, medida mediante los dominios y las puntuaciones de los componentes del cuestionario SF-36 v2 y la escala visual analógica (EVA) y el índice del cuestionario EQ-5D-5L;
    4. Porcentaje de paciente y tiempo transcurrido hasta sufrir una recaída; la recaída se define como la aparición de, como mínimo, un ítem principal en la escala BVAS, o de tres o más ítems secundarios, o de uno o dos ítems secundarios en dos visitas consecutivas, después de haber alcanzado anteriormente la remisión (BVAS = 0) en el estudio;
    5. En los pacientes con nefropatía en el periodo basal (según el componente renal de la BVAS), la variación de la FGe desde el periodo basal durante 52 semanas;
    6. En los pacientes con nefropatía en el periodo basal (según el componente renal de la BVAS), el cambio porcentual en el CACO desde el periodo basal durante 52 semanas;
    7. En los pacientes con nefropatía en el periodo basal (según el componente renal de la BVAS), el cambio porcentual en el cociente MCP-1:creatinina urinaria desde el periodo basal durante 52 semanas;
    8. La variación del índice VDI respecto al periodo basal durante 52 semanas.
    Los criterios de valoración de la seguridad, excepto la toxicidad inducida por glucocorticoides, incluyen:
    1. Incidencia de acontecimientos adversos graves aparecidos durante el tratamiento, acontecimientos adversos y retiradas ocasionadas por acontecimientos adversos;
    2. Cambio respecto al periodo basal y fluctuaciones respecto al periodo basal en todos los parámetros analíticos de seguridad;
    3. Cambio respecto al periodo basal en las constantes vitales; e
    4. Incidencia de variaciones en el ECG clínicamente significativas respecto al periodo basal.

    Criterio de Valoración de Farmacocinética
    Las concentraciones plasmáticas de CX168 (y metabolito) en plasma se utilizarán para calcular las conccentraciones mínimas (Cmin) en el transcurso del ensayo clínico.
    Criterio de Valoración de Farmacodinámica
    Se evaluarían los siguientes criterios de Valoración de Farmacodinámica
    1. Cambio y el porcentaje de cambio desde el inicio, de biomarcadores cistatina C como, por ejemplo, fragmentos del complemento, quimiocinas inflamatorias y los niveles de citoquinas, en plasma.
    2. Cambio y el porcentaje de cambio desde el inicio de los biomarcadores de orina, como los marcadores de daño renal y la inflamación (por ejemplo, NGAL y KIM-1), CD163 soluble, fragmentos del complemento, los niveles de quimioquinas y citoquinas inflamatorias;
    3. Cambio en el recuento de CBC (especialmente leucocitos, neutrófilos y linfocitos) y el subconjunto de linfocitos cuenta como células B, células T y células asesinas naturales;
    4. Cambio del valor inicial en la expresión de genes de células sanguíneas como marcadores del estado funcional de los neutrófilos.

    El efecto del polimorfismo en marcadores genéticos, así como el polimorfismo C5aR se investigarán.
    E.5.2.1Timepoint(s) of evaluation of this end point
    various, refer to information in E.5.2
    Varios, Consulte la información 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 concerned11
    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
    Última Visita del Úlitmo Paciente
    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: 3
    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
    Adolescentes
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state40
    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
    Ninguno-Tratamiento normal esperado para esa patologia
    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 Decision2017-03-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-03-21
    P. End of Trial
    P.End of Trial StatusCompleted
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