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    Summary
    EudraCT Number:2012-003788-23
    Sponsor's Protocol Code Number:ACE-011-REN-002
    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:2013-10-18
    Trial results View 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 number2012-003788-23
    A.3Full title of the trial
    A Phase 2 Multicenter, Randomized, Open Label, Multiple Dose Study of Intravenous and Subcutaneous Administration of Sotatercept (ACE-011) in Subjects with End-Stage Kidney Disease on Hemodialysis Switched from Erythropoiesis Stimulating Agents with Staggered Dose Group Escalation in Part 1 Followed by a Parallel Group, Active Controlled Study of Selected Dose(s) and Regimen(s) in Part 2: to Evaluate the Pharmacokinetics, Safety, Tolerability, Efficacy, Dosing Regimen, and Pharmacodynamics of Sotatercept
    Estudio de fase 2 multicéntrico, aleatorizado, abierto, de dosis múltiples de sotatercept (ACE-011) administrado por vía intravenosa y subcutánea, en sustitución de fármacos estimuladores de la hematopoyesis, en pacientes con nefropatía renal terminal en
    hemodiálisis mediante grupos de aumento escalonado de la dosis en la parte 1, seguido de un estudio de grupos paralelos y con control activo de la(s) dosis y pauta(s) seleccionada(s) en la parte 2, para evaluar la farmacocinética, seguridad, tolerabilidad, eficacia, pauta posológica y
    farmacodinamia de sotatercept
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study of sotatercept given by injection for evaluating the safety, pharmacokinetics (effect of body on drug), and effect on anemia and bone disorder in people with end stage kidney disease on hemodialysis that are switched from erythropoiesis stimulating agents (medication to treat anemia) to sotatercept.
    Un estudio de sotatercept administrado por inyección para la evaluación de la seguridad, farmacocinética (efecto del cuerpo sobre los medicamentos), y el efecto sobre la anemia y la enfermedad ósea en personas con enfermedad renal terminal en hemodiálisis que se cambiaron de agentes estimulantes de la eritropoyesis (medicamento para tratar la anemia) a sotatercept
    A.4.1Sponsor's protocol code numberACE-011-REN-002
    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 SponsorCelgene Corporation
    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 supportCelgene Corporation
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCelgene Corporation
    B.5.2Functional name of contact pointClinical Trial Disclosure
    B.5.3 Address:
    B.5.3.1Street Address9225 Indian Creek Parkway, Suite 900
    B.5.3.2Town/ cityOverland Park, Kansas
    B.5.3.3Post code66210
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1-888-260-1599
    B.5.5Fax number+1 913-266-0394
    B.5.6E-mailClinicalTrialDisclosure@celgene.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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameSotatercept
    D.3.2Product code ACE-011
    D.3.4Pharmaceutical form Lyophilisate for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNSotatercept
    D.3.9.2Current sponsor codeACE-011
    D.3.9.3Other descriptive nameActRIIA-IgG1Fc
    D.3.10 Strength
    D.3.10.1Concentration unit mg/kg milligram(s)/kilogram
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number0.3
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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 No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameSotatercept
    D.3.2Product code ACE-011
    D.3.4Pharmaceutical form Lyophilisate for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNSotatercept
    D.3.9.2Current sponsor codeACE-011
    D.3.9.3Other descriptive nameActRIIA-IgG1Fc
    D.3.10 Strength
    D.3.10.1Concentration unit mg/kg milligram(s)/kilogram
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number0.4
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    End-stage kidney disease (ESKD) who are on hemodialysis and will be switched from their current stable treatment with erythropoiesis stimulating agent (ESA) to sotatercept.
    Enfermedad renal terminal (ERT) que están en hemodiálisis y se cambiarán de su tratamiento estable actual con el factor estimulador de la eritropoyesis (FEE) a sotatercept.
    E.1.1.1Medical condition in easily understood language
    Anemia due to kidney disease in people on hemodialysis
    Anemia por enfermedad renal en personas en hemodiálisis
    E.1.1.2Therapeutic area Not possible to specify
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    E.1.2Level LLT
    E.1.2Classification code 10064848
    E.1.2Term Chronic kidney disease
    E.1.2System Organ Class 100000004857
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Part 1
    To determine the multiple dose pharmacokinetics, safety, and tolerability of IV and SQ dosing of sotatercept administered at each dose level.
    Part 2
    To determine the safety and efficacy of the selected starting dose(s), route(s) of administration, and dose modification regimen(s) on maintenance of hemoglobin concentrations between baseline and the Evaluation Phase
    Parte 1
    -Determinar la FC de dosis múltiples, seguridad y tolerabilidad de sotatercept administrado por vía IV y SC con cada nivel de dosis.
    Parte 2
    -Determinar la seguridad y eficacia de las dosis iniciales seleccionadas, vías de administración de sotatercept y pautas de modificación de la dosis para mantener la concentración de hemoglobina entre el momento basal y la fase de evaluación.
    E.2.2Secondary objectives of the trial
    Part 1
    ?To determine hemoglobin response at different dose levels
    ?To determine pharmacodynamic (hemoglobin) relationship between IV and SQ doses of sotatercept at different dose levels
    ?To select a starting dose(s) and route(s) of administration for switching subjects from ESA for Part 2
    Part 2
    ?To determine the effect of sotatercept on bone mineral density (BMD)
    ?Other secondary objectives are:
    -To determine the safety and efficacy of the selected starting dose(s), route(s) of administration, and dose modification regimen(s) on maintenance of hemoglobin concentrations from baseline through the end of the Maintenance Phase
    -To determine hemoglobin response during the Evaluation Phase and end of the Maintenance Phase
    -To determine the pharmacodynamic effects on parameters of : Mineral metabolism,Erythropoietin,Bone histology,Vascular calcification,Iron metabolism
    To determine the multiple dose pharmacokinetics of sotatercept at the selected dose(s)
    Parte1
    -Determinar respuesta de Hg con diferentes niveles de dosis
    -Determinar relación farmacodinámica (Hg) entre dosis IV y SC de sotatercept con diferentes niveles de dosis
    -Seleccionar una o más dosis iniciales y vías de administración de sotatercept para sustituir los FEE en parte 2
    Parte2
    -determinar el efecto de sotatercept sobre la DMO
    -Otros objetivos secundarios son:
    -Determinar seguridad y eficacia de las dosis iniciales seleccionadas,vías de administración de sotatercept y pautas de modificación de dosis para mantener la concentración de hemoglobina entre el momento basal y el final de la fase de mantenimiento
    -Determinar la respuesta de hemoglobina durante la fase de evaluación y al final de la fase de mantenimiento
    -Determinar los efectos farmacodinámicos sobre parámetros del
    metabolismo mineral, eritropoyetina, histología ósea, calcificación
    vascular y metabolismo del hierro.
    -Determinar la FC de dosis múltiples de sotatercept con las dosis
    seleccionadas
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Males or females ? 18 years of age at the time of signing informed consent document.
    2.Clinically stable in the judgment of the investigator.
    3.Subjects on at least 6 hours of hemodialysis per week, for at least 12 weeks before screening and during the study.
    4.Subjects must be on a stable IV or SQ dose of ESA (excluding methoxy polyethylene glycol epoetin-beta) to maintain hemoglobin. A stable dose is defined as ? 50% change from the maximum prescribed weekly ESA dose ([max-min]/max ? 0.5) and no change in frequency during the last 6 weeks prior to randomization unless the dose is held for high hemoglobin. If ESA dose is held for high hemoglobin, subject must be restarted on a stable dose (defined as ? 50% change from prior dose). Maximum allowed ESA dose must be equivalent to epoetin ? 500 IU/kg/week, or darbepoetin ? 95 mcg/week.
    5.A mean hemoglobin concentration ? 10 to ? 12 g/dL (? 100 to ? 120 g/L) obtained from three consecutive (each done on different days) predialysis hemoglobin concentrations, with the last hemoglobin concentration done within the 7 days prior to randomization (if local laboratory values are used, they should be obtained consistently from the same laboratory).
    6.Subjects must have adequate iron status defined as one transferrin saturation ? 20% prior to randomization.
    7.A Kt/V ? 1.2 or urea reduction ratio ? 65% at screening, (historical values within 1 month prior to screening are acceptable).
    8.The subject has one PTH concentration ? 1000 pg/mL, one phosphorus concentration ? 7 mg/dL, one total albumin-corrected calcium concentration > 8.0 mg/dL to < 10.5 mg/dL , and one magnesium concentration ? 1.5 mEq/L prior to randomization.
    9.A BMI value ? 18.5 kg/m2 at screening. Weight at screening will be collected postdialysis (dry weight) for BMI calculation.
    10.Female subjects of childbearing potential participating in the study are to use highly effective methods of birth control during study participation. Females of childbearing potential must have a negative serum pregnancy test prior to randomization. In addition, subjects must be educated concerning measures to be used to prevent pregnancy and potential toxicities. (A female of childbearing potential is a sexually mature woman who has not undergone a hysterectomy or bilateral oophorectomy; or who has not been postmenopausal for at least 24 consecutive months ie, who has had menses at some time in the preceding 24 months).
    Some highly effective methods of birth control include:
    ?Oral contraceptives, intrauterine device, tubal ligation or vasectomized partner
    OR
    ?Two forms of barrier method birth control, e.g., a latex condom PLUS a diaphragm with spermicide OR a latex condom PLUS a contraceptive sponge with spermicide. If a non-latex condom is used, it cannot be made out of natural (animal) membrane
    11.Male subjects (including those who have had a vasectomy) who engage in activity in which conception is possible must use barrier contraception (male latex condom or non latex condom NOT made out of natural [animal] membrane [for example, polyurethane]) while participating in the study.
    12.Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures are conducted.
    13.Able to adhere to the study visit schedule and comply with all protocol requirements.
    1. Varones o mujeres con una edad mínima de 18 años en el momento de firmar el documento de consentimiento informado.
    2. Clínicamente estables a criterio del investigador.
    3. En hemodiálisis durante un mínimo de 6 horas por semana, durante al menos 12 semanas antes de la selección y durante el estudio.
    4. En tratamiento con una dosis IV o SC estable de FEE (excepto metoxipolietilenglicol epoetina beta) para mantener la hemoglobina. Se define dosis estable como una modificación <= 50 % con respecto a la dosis semanal prescrita máxima del FEE ([máx-mín]/máx <= 0,5) y sin modificación de la frecuencia durante las 6 semanas previas a la aleatorización, a menos que se aplace la administración por una hemoglobina elevada. En caso de que se aplace la administración de FEE por una hemoglobina
    elevada, el paciente deberá reanudarla con una dosis estable (definida como una modificación <= 50 % con respecto a la dosis previa). La dosis máxima permitida del FEE ha de ser equivalente a epoetina <= 500 UI/kg/semana o darbepoetina <= 95 ?g/semana.
    5. Concentración media de hemoglobina >= 10 y <= 12 g/dl (>= 100 y <= 120 g/l) obtenida a partir de tres concentraciones de hemoglobina antes de la diálisis consecutivas (todas ellas en días diferentes), con obtención de la última concentración de hemoglobina en los 7 días previos a la aleatorización (cuando se utilicen valores del laboratorio local, deberán obtenerse de forma sistemática del mismo laboratorio).
    6. Estado del hierro adecuado, definido como una saturación de transferrina >= 20 % antes de la aleatorización.
    7. Kt/V >= 1,2 o cociente de reducción de la urea >= 65 % en la fase de selección (podrán utilizarse valores históricos obtenidos en el mes previo a la selección).
    8. Disponibilidad de una concentración de PTH <= 1000 pg/ml (<= 1000 ng/l), una concentración de fósforo <= 7 mg/dl (<= 2,26 mmol/l), una concentración de calcio total corregida por la albúmina > 8,0 y < 10,5 mg/dl (> 2,0 y < 2,63 mmol/l) y una concentración de magnesio >= 1,5 mEq/l (>= 0,75 mmol/l) antes de la aleatorización.
    9. Valor de IMC >= 18,5 kg/m2 en la fase de selección. En la fase de selección, el peso se medirá después de la diálisis (peso seco) para calcular el IMC.
    10. Las mujeres en edad fértil que participen en el estudio tendrán que utilizar métodos anticonceptivos muy eficaces durante su participación. Las mujeres en edad fértil deberán dar negativo en una prueba de embarazo en suero realizada antes de la aleatorización. Además, se informará a las pacientes de las medidas a adoptar para evitar embarazos y posible toxicidad. (Se entiende por mujer en edad fértil a una mujer sexualmente madura que no se ha sometido a una histerectomía u ovariectomía bilateral o que no lleva posmenopáusica un mínimo de 24 meses consecutivos, es decir, que ha tenido la menstruación en algún momento durante los 24 meses precedentes).
    Algunos métodos anticonceptivos muy eficaces son:
    ? Anticonceptivos orales, dispositivo intrauterino, ligadura de trompas o pareja vasectomizada
    O BIEN
    ? Dos métodos anticonceptivos de barrera, por ejemplo, preservativo de látex MÁS diafragma con espermicida O preservativo de látex MÁS esponja anticonceptiva con espermicida. En caso de utilizar un preservativo que no sea de látex, no podrá estar hecho de membrana natural (animal).
    11. Los varones (aunque se hayan sometido a una vasectomía) que mantengan actividad sexual en la que haya posibilidad de concepción deberán utilizar métodos anticonceptivos de barrera (preservativo de látex o preservativo que no sea de látex NO hecho de membrana natural [animal] [por ejemplo, poliuretano]) durante su participación en el estudio.
    12. Comprensión y firma voluntaria de un documento de consentimiento informado antes de que se realice ninguna evaluación o procedimiento relacionado con el estudio.
    13. Capacidad de cumplir el calendario de visitas del estudio y todos los requisitos del protocolo.
    E.4Principal exclusion criteria
    1. Non renal causes of anemia due to active inflammatory disease such as systemic lupus erythematosus, active liver disease, hypersplenism, gastrointestinal bleeding, osteomyelitis, tuberculosis, lung abscess, etc.
    2. Subjects on peritoneal dialysis.
    3. Systemic hematological disease such as sickle cell anemia, myelodysplastic syndromes, hematological malignancy, myeloma, hemolytic anemia.
    4. High sensitivity C-reactive protein > 50 mg/L at screening.
    5. Subject has alanine transaminase (ALT) or aspartate transaminase (AST) laboratory
    values > 2 times the upper limit of normal (ULN) at screening.
    6. Uncontrolled diabetes mellitus (HbA1c > 9) at screening.
    7. Uncontrolled hypertension defined as mean of home systolic blood pressure > 160 mm Hg or mean of home diastolic blood pressure > 90 mm Hg calculated once during the screening period prior to randomization (A mean of 4 consecutive days of home systolic and diastolic blood pressure values taken during a 7-day window in the screening period prior to randomization, with a minimum of 6 values for calculating the mean are required - 3 taken from a single morning set of measurements, and 3 taken from a single evening set of measurements. Note: Both the mean systolic and diastolic home blood pressure eligibility must be met).
    8. Subjects with heart failure as classified by the New York Heart Association (NYHA) classification of 3 or higher, (see Appendix E).
    9. Compromised venous access for the purpose of hemodialysis or obtaining blood samples for the study.
    10. Subjects taking high dose vitamin D or calcimimetic medications (such as cinacalcet ? 120 mg once daily; paricalcitol 0.24 mcg/kg three times weekly; doxercalciferol 6 mcg three times weekly) within 3 months prior to screening and during the course of the study.
    11. Subjects taking drugs that affect bone turnover (see prohibited concomitant therapy Section 9.2) within 3 months prior to screening and during the course of the study.
    12. ESKD due to malignancy.
    13. History of malignancy (except excised and cured non-melanoma skin cancer, or cervical carcinoma in situ that was surgically ablated more than 1 year ago).
    14. Active serious infection or history of a recurrent serious infection that is likely to recur during the study, with the last infection within 3 months prior to the screening visit (immunosuppressants and high dose corticosteroids are excluded eg, prednisone ? 10 mg per day or equivalent, see Section 9.2).
    15. Subject has human immunodeficiency virus (HIV).
    16. Major surgeries or surgeries (excludes vascular access surgery) requiring hospitalization within 28 days prior to randomization and/or expected during the course of the study (subjects must have, in the judgment of the investigator, completely recovered from any previous surgery prior to randomization).
    17. Anticipated or scheduled living donor renal transplant during the course of the study.
    18. Any RBC transfusions within 8 weeks prior to screening.
    19. Life expectancy < 1 year.
    20. History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational product or to the specific iron products needed to normalize iron levels for subjects or to tetracycline (or appropriate substitute) for subjects who consent to bone biopsy.
    21. Subjects who received treatment with another investigational drug or device within 28 days prior to randomization, or if the half-life of the previous product is known, within 5 times the half life prior to dosing, whichever may be longer.
    22. Pregnant or breast feeding females.
    23. Any significant medical condition, laboratory abnormality, or psychiatric illness which in the judgment of the investigator places the subject at unacceptable risk if he/she were to participate in the study (subjects who consent to bone biopsies should be evaluated for routine pre-operative examination).
    1. Causas extrarrenales de anemia, entre ellas, enfermedad inflamatoria activa, como lupus eritematoso sistémico, hepatopatía activa, hiperesplenismo, hemorragia digestiva, osteomielitis, tuberculosis, absceso pulmonar, etc.
    2. En tratamiento con diálisis peritoneal.
    3. Enfermedad hematológica sistémica, como anemia falciforme, síndrome mielodisplásico, neoplasia hematológica maligna, mieloma o anemia hemolítica.
    4. Proteína C reactiva de alta sensibilidad > 50 mg/l en la fase de selección.
    5. Valores de alanina transaminasa (ALT) o aspartato transaminasa (AST) > 2 veces el límite superior de la normalidad (LSN) en la fase de selección.
    6. Diabetes mellitus no controlada (HbA1c > 9 %) en la fase de selección.
    7. Hipertensión no controlada, definida como una presión arterial sistólica domiciliaria media > 160 mm Hg o una presión arterial diastólica domiciliaria media > 90 mm Hg calculada una vez durante el período de selección antes de la aleatorización (media de un intervalo de 4 días de valores de presión arterial sistólica y diastólica domiciliaria obtenidos con un margen de 7 días durante el período de selección antes de la aleatorización, con un mínimo de 6 valores para calcular la media exigida, 3 obtenidos a
    partir de un solo conjunto de determinaciones al despertarse y 3 a partir de un único conjunto de determinaciones al acostarse. Nota: Han de cumplirse ambos criterios de elegibilidad en relación con la presión arterial sistólica y diastólica domiciliaria media).
    8. Insuficiencia cardíaca en clase 3 o superior según la clasificación de la New York Heart Association (NYHA) (véase el apéndice E).
    9. Acceso venoso difícil para la hemodiálisis o para obtener muestras de sangre para el estudio.
    10. Tratamiento con vitamina D en dosis altas o calcimiméticos (como cinacalcet >= 120 mg una vez al día, paricalcitol 0,24 ?g/kg tres veces por semana o doxercalciferol 6 ?g tres veces por semana) en los 3 meses previos a la selección y durante el estudio.
    11. Tratamiento con fármacos que afecten al recambio óseo (véanse los tratamientos concomitantes prohibidos en la sección 9.2) en los 3 meses previos a la selección y durante el estudio.
    12. NT debida a una neoplasia maligna.
    13. Antecedentes de neoplasia maligna (excepto cáncer de piel distinto del melanoma extirpado y curado o carcinoma de cuello uterino in situ extirpado quirúrgicamente hace más de 5 años).
    14. Infección grave activa o antecedentes de una infección grave recurrente con probabilidad de reaparecer durante el estudio, con la última infección en los 3 meses previos a la visita de selección.
    15. Quedan excluidos los inmunodepresores y corticosteroides en dosis altas, por ejemplo, prednisona >= 10 mg al día o equivalente (véase la sección 9.2).
    16. Antecedentes de infección por el virus de la inmunodeficiencia humana (VIH).
    17. Intervenciones de cirugía mayor o intervenciones quirúrgicas (excluida la cirugía de acceso vascular) que precisen hospitalización en los 28 días previos a la aleatorización o que estén previstas durante el estudio (los pacientes tendrán que haberse recuperado completamente, en opinión del investigador, de cualquier intervención quirúrgica previa antes de la aleatorización).
    18. Trasplante renal de donante vivo previsto o programado durante el estudio.
    19. Transfusiones de hematíes en las 8 semanas previas a la selección.
    20. Esperanza de vida inferior a un año.
    21. Antecedentes de reacciones alérgicas o anafilácticas graves o de hipersensibilidad a proteínas recombinantes, a los excipientes del producto en investigación, a los productos de hierro específicos que se necesiten para normalizar las concentraciones de hierro en los pacientes o a la tetraciclina (o un sustituto adecuado) en los pacientes que otorguen su consentimiento para someterse a biopsias óseas (Nota: Solo se realizarán biopsias óseas en la parte 2).
    22. Tratamiento con otro fármaco o dispositivo en investigación en los 28 días previos a la aleatorización o, si se conoce la semivida del producto anterior, en el período equivalente a 5 veces la semivida antes de la administración, lo que sea más largo.
    23. Embarazo o lactancia.
    24. Cualquier proceso médico, anomalía analítica o enfermedad psiquiátrica importante que, en opinión del investigador, suponga un riesgo inaceptable para el paciente en caso de participar en el estudio (los pacientes que otorguen su consentimiento para someterse a biopsias óseas tendrán que ser evaluados mediante un examen preoperatorio sistemático).
    E.5 End points
    E.5.1Primary end point(s)
    Part 1
    ?Pharmacokinetic parameters, including Observed maximum concentration (Cmax), Time to Cmax (Tmax), Area under the concentration-time curve over the 28-day dosing interval (AUC28d), Terminal half-life (t1/2,z)

    Part 2
    ?Change in mean hemoglobin concentration between baseline and the Evaluation Phase (baseline hemoglobin value is mean of three consecutive hemoglobin concentrations with the last hemoglobin concentration done within the 7 days prior to randomization and the value obtained on the day of randomization. The Evaluation Phase hemoglobin value is mean of hemoglobin concentrations from Day 176 to Day 197 [Visit 16 to 19])
    Parte 1
    -Parámetros farmacocinéticos, entre ellos, concentración máxima observada (Cmax), tiempo en alcanzar la Cmax (Tmax), área bajo la curva de concentración-tiempo durante el intervalo de administración de 28 días (AUC28d) y semivida terminal (t1/2,z).
    Parte 2
    -Variación de la concentración media de hemoglobina entre el momento basal y la fase de evaluación (el valor basal de hemoglobina es la media de 3 concentraciones de hemoglobina consecutivas, con la última concentración de hemoglobina determinada en los 7 días previos a la aleatorización y el valor
    obtenido el día de aleatorización). El valor de hemoglobina de la fase de evaluación es la media de las concentraciones de hemoglobina obtenidas entre los días 176 y 197 (entre las visitas 16 y 19).
    E.5.1.1Timepoint(s) of evaluation of this end point
    as specified in Section E.5.1
    Como se especifica en la sección 5.1
    E.5.2Secondary end point(s)
    Part 1
    ?Proportion of subjects able to maintain a mean (Visit 14 to 17) hemoglobin concentration ? 10 to ? 12 g/dL without the need for rescue at each dose level (mean hemoglobin value is a mean of hemoglobin concentrations from Day 99 [Visit 14] to Day 113 [Visit 17])
    ?Change in mean hemoglobin concentration between baseline and Visit 14 to 17 at each dose level (baseline hemoglobin value is mean of three consecutive hemoglobin concentrations with the last hemoglobin concentration done within the 7 days prior to randomization and the value obtained on the day of randomization. Visit 14 to 17 hemoglobin value is a mean of hemoglobin concentrations from Day 99 [Visit 14] to Day 113 [Visit 17]))

    Part 2
    ?The key secondary endpoint is the percent change in volumetric bone mineral density (vBMD) from baseline measured by quantitative computed tomography (QCT) at Day 393 (Visit 26)
    Other Secondary Endpoints:
    ?Change in mean hemoglobin concentration between baseline and the end of the Maintenance Phase (baseline hemoglobin value is mean of three consecutive hemoglobin concentrations with the last hemoglobin concentration done within the 7 days prior to randomization and the value obtained on the day of randomization. Maintenance Phase hemoglobin value is mean of hemoglobin concentrations from Day 365 to Day 393 [Visit 25 to 26])
    ?Proportion of subjects able to maintain a mean (Visit 16 to 19) hemoglobin concentration ? 10 to ? 12 g/dL without the need for rescue during the Evaluation Phase (Evaluation Phase hemoglobin value is mean hemoglobin concentrations from Day 176 to Day 197 [Visit 16 to 19]) and the Maintenance Phase (Maintenance Phase hemoglobin value is mean of hemoglobin concentrations from Day 365 to Day 393 [Visit 25 to 26])
    Parte 1
    -Proporción de pacientes capaces de mantener una concentración media (visitas 14 a 17) de hemoglobina >= 10 y <= 12 g/dl (>= 100 y <= 120 g/l) sin necesidad de rescate con cada nivel de dosis (el valor medio de hemoglobina es la media de las concentraciones de hemoglobina obtenidas entre los días 99 [visita 14] y 113 [visita 17]).
    - Variación de la concentración media de hemoglobina entre el momento basal y la visita 14 a 17 con cada nivel de dosis (el valor basal de hemoglobina es la media de 3 concentraciones de hemoglobina consecutivas, con la última concentración de hemoglobina determinada en los 7 días previos a la aleatorización y el valor obtenido el día de aleatorización; el valor de hemoglobina en la visita 14 a 17 es la media de las concentraciones de hemoglobina obtenidas entre los días 99 [visita 14] y 113 [visita 17]).
    Parte 2
    - El criterio de valoración secundario fundamental es la variación porcentual de la densidad mineral ósea volumétrica (DMOv) con respecto al momento basal, determinada mediante tomografía computarizada cuantitativa (TCC) el día 393 (visita 26).
    Otros criterios de valoración secundarios:
    - Variación de la concentración media de hemoglobina entre el momento basal y el final de la fase de mantenimiento (el valor basal de hemoglobina es la media de 3 concentraciones de hemoglobina consecutivas, con la última concentración de hemoglobina determinada en los 7 días previos a la aleatorización y el valor obtenido el día de aleatorización. Eel valor de hemoglobina de la fase de mantenimiento es la media de las concentraciones de hemoglobina obtenidas entre los días 365 y 393 [entre las visitas 25 y 26]).
    - Proporción de pacientes capaces de mantener una concentración media (visitas 16 a 19) de hemoglobina >= 10 y <= 12 g/dl (>= 100 y <= 120 g/l) sin necesidad de rescate durante la fase de evaluación (el valor de hemoglobina de la fase de evaluación es la media de las concentraciones de hemoglobina obtenidas entre los días 176 y 197 [entre las visitas 16 y 19]) y la fase de mantenimiento (el valor de hemoglobina de la fase de mantenimiento es la media de las concentraciones de hemoglobina obtenidas entre los días 365 y 393 [entre las visitas 25 y 26]).
    E.5.2.1Timepoint(s) of evaluation of this end point
    as specified in Section E.5.2
    Como se especifica en la sección 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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) 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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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 No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Dosis de FEE según régimen del paciente durante el screening (IV o SC)
    ESA dose as per subject's regimen during screening (IV or SQ)
    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 concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA70
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    See protocol
    Ver protocolo
    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 months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months6
    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: 201
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 84
    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 state70
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 285
    F.4.2.2In the whole clinical trial 285
    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)
    Please refer to the protocol
    Porfavor ver el protocolo
    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 Decision2013-10-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-10-07
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-08-23
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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