E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Low or Intermediate-1 Risk Myelodysplastic Syndrome (MDS) |
síndrome mielodisplásico de riesgo
bajo o intermedio-1. |
|
E.1.1.1 | Medical condition in easily understood language |
Low or Medium Risk Myelodysplastic Syndrome (MDS) |
síndrome mielodisplásico de riesgo
bajo o intermedio (SMD). |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 13.1 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10028536 |
E.1.2 | Term | Myelodysplastic syndromes |
E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the superiority of darbepoetin alfa treatment compared with placebo on the proportion of subjects achieving International Working Group (IWG) erythroid response during the 24-week double-blind treatment period, in anaemic subjects with low or intermediate-1 risk MDS.
|
Evaluar la superioridad del tratamiento con Darbepoetin alfa comparado con el tratamiento con placebo en la proporción de sujetos que alcancen respuesta eritroide según el International Working Group (IWG) (Cheson et al., 2006) durante un periodo de tratamiento de 24 semanas con doble ciego en sujetos anémicos con SMD de riesgo bajo o intermedio 1. |
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E.2.2 | Secondary objectives of the trial |
• To assess the superiority of darbepoetin alfa versus placebo on the incidence of RBC transfusion during the double-blind treatment period
• To assess safety of darbepoetin alfa compared with placebo
• To assess the health-related qualify of life (HRQOL) scores of darbepoetin alfa compared with placebo, and to assess the effect of haemoglobin change on HRQOL scores
|
• Evaluar la superioridad de la Darbepoetin alfa frente al placebo en la incidencia de transfusiones de eritrocitos durante el periodo de tratamiento con doble ciego.
• Evaluar la seguridad de la Darbepoetin alfa comparada con placebo.
• Evaluar las puntuaciones de la calidad de vida relacionada con la salud (CVRS) de la Darbepoetin alfa en comparación con el placebo, y evaluar el efecto del cambio de hemoglobina en las puntuaciones de CVRS.
|
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Low or intermediate-1 risk MDS patients per IPSS at the time of randomization, as determined by complete blood count (CBC) during screening and bone marrow examination and marrow cytogenetic analysis, performed within 16 weeks prior to randomisation. Subject cannot have been rendered low or intermediate-1 risk by prior disease modifying therapy
- World Health Organization (WHO) classification of refractory anaemia (RA), refractory anaemia with ring sideroblasts (RARS), refractory cytopenias with multilineage dysplasia (RCMD), MDS unclassified (MDS-U), MDS with isolated del(5q) (5q- syndrome) or refractory anaemia with excess blasts-1 (RAEB-1)
-Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 assessed during screening
-Haemoglobin level ≤10.0 g/dL as assessed by the local laboratory; sample obtained within 7 days prior to randomisation (retest during screening is acceptable).
-Adequate transferrin saturation (Tsat) (≥ 15%) and serum ferritin (≥ 10 ng/mL) as assessed during screening (supplementation and retest during screening is acceptable)
-Adequate serum folate (≥ 4.5 nmol/L [ ≥2.0 ng/mL]) or RBC folate (≥317 nmol/L [ ≥140 ng/mL]) as assessed by the local laboratory during screening (supplementation and retest during screening is acceptable)
- Adequate vitamin B12 (≥148 pmol/L ≥200 pg/mL]) as assessed by the local laboratory during screening (supplementation and retest during screening is acceptable)
-18 years of age or older
- Subject or subject’s legally acceptable representative has provided informed consent
|
-Sujetos con SMD de riesgo bajo o intermedio 1 según IPSS en el momento de la aleatorización, según se determina mediante hemograma completo (HC) durante la selección y de examen de la médula ósea y análisis de la citogenética de la médula realizados dentro de las 16 semanas anteriores a la aleatorización. Los pacientes no pueden haberse vuelto de riesgo bajo o intermedio mediante tratamiento anterior modificador de la enfermedad.
-Clasificación de la Organización Mundial de la Salud (OMS) de anemia refractaria (AR), anemia refractaria con sideroblastos en anillo (ARSA), citopenias refractarias con displasia multilinaje (CRDM), SMD no clasificado (SMD-NC), SMD con del(5q) aislado (síndrome 5q-) o anemia refractaria con exceso de blastos-1 (AREB-1). |
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E.4 | Principal exclusion criteria |
- Previously diagnosed with intermediate-2 or high risk MDS per IPSS
- Therapy-related or secondary MDS
- History of acute leukemia
- Evidence of bone marrow collagen fibrosis
- Inherited anaemia, active hemorrhage, red cell aplasia, haemolytic anaemia
- History of malignancies other than curatively treated non-melanoma skin or in situ carcinoma within 5 years prior to screening
- History of thrombosis within 6 months prior to randomisation
- Previous bone marrow or stem cell transplantation
- Uncontrolled angina, uncontrolled heart failure, or uncontrolled cardiac arrhythmia as determined by the investigator at screening. Subjects with known myocardial infarction within 6 months prior to randomisation.
- Uncontrolled hypertension as determined by the investigator at screening
- Clinically significant systemic infection or uncontrolled chronic inflammatory disease
- History of seizure disorder
- Previous or ongoing use of ESA therapy, eg, rHuEpo, darbepoetin alfa
- High transfusion demand: receiving a total of ≥ 4 units of RBC transfusion during either of 2 consecutive 8-week periods
- Received any RBC transfusion within 14 days prior to randomisation
- Received cytotoxic chemotherapy for any oncologic indication or planning to receive cytotoxic chemotherapy during the double-blind treatment period of the study
- Received biologic response modifiers
- Received myeloablative or craniospinal radiation within 30 days prior to randomisation or planning to receive myeloablative or craniospinal radiation during the double-blind treatment period of the study
- Received G-CSF therapy within 30 days prior to randomisation or planning to receive G-CSF therapy during the double-blind treatment period of the study
- Abnormal renal function
- Abnormal liver function
- Serum endogenous EPO level > 500 mU/mL at screening
- Known seropositivity for human immunodeficiency virus (HIV) or diagnosis of Acquired Immunodeficiency Syndrome (AIDS), positive for hepatitis B surface antigen, or seropositive for hepatitis C virus
- Subjects with active ethanol abuse
- Currently enrolled in another investigational device or drug study, or less than 30 days since ending another investigational device or drug study(s), or receiving other investigational agent(s)
- Female subject is not willing to use highly effective contraception during treatment and for at least 1 month after the end of treatment
- Female subject is pregnant or planning to become pregnant within 1 month after the end of treatment
- Subject has known sensitivity to any of the products to be administered during dosing
- Subject has known sensitivity to any of the products to be administered during dosing
- Subject has previously been randomised into this study
- Subject will not be available for protocol required study visits, to the best of the subject and investigator’s knowledge
- Subject has any kind of disorder that, in the opinion of the investigator, may compromise the ability of the subject to give written informed consent and/or to comply with all required study procedures
- Confirmed history of neutralising antibody activity to rHuEpo or darbepoetin alfa
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- Diagnosticado anteriormente con SMD de riesgo intermedio 2 o alto mediante IPSS.
SMD relacionado con el tratamiento o secundario.
- Antecedentes de leucemia aguda.
- Evidencia de fibrosis de colágeno de la médula ósea.
- Anemia heredada, hemorragia activa, aplasia eritrocitaria, anemia hemolítica.
- Antecedentes de neoplasias malignas que no sean carcinoma in situ o carcinoma cutáneo no melanoma tratados de forma curativa durante los 5 años anteriores a la selección.
Antecedentes de trombosis en los 6 meses anteriores a la aleatorización.
- Trasplante anterior de médula ósea o de células madre.
- Angina no controlada, insuficiencia cardíaca no controlada, o arritmias cardíacas no controladas según lo determine el investigador en la selección. Sujetos con infarto de miocardio conocido dentro de los 6 meses anteriores a la aleatorización.
- Hipertensión no controlada, según lo determine el investigador en la selección.
- Infección sistémica clínicamente significativa o enfermedad inflamatoria crónica no controlada (es decir, artritis reumatoide, enfermedad inflamatoria intestinal) según lo determine el investigador en la selección.
- Antecedentes de trastornos convulsivos.
Uso anterior o actual de tratamiento AEE, p. ej., rHuEpo, Darbepoetin alfa.
- Alta demanda de transfusiones: recibiendo un total de ≥ 4 unidades de transfusiones de eritrocitos durante los 2 periodos consecutivos de 8 semanas (es decir, días -113 a -57 o días -56 a 0) antes de la aleatorización.
- Que haya recibido cualquier transfusión de eritrocitos dentro de los 14 días anteriores a la aleatorización.
- Que haya recibido quimioterapia citotóxica para cualquier indicación oncológica o que tenga planeado recibir quimioterapia citotóxica durante el periodo de tratamiento con doble ciego del estudio.
- Que haya recibido modificadores de la respuesta biológica
- Que haya recibido radiación mieloablativa o craneoespinal o que tenga planificado recibir radiación mieloablativa o craneoespinal durante el periodo de tratamiento con doble ciego del estudio
- Que hayan recibido tratamiento con G-CSF durante los 30 días anteriores a la aleatorización
- Función renal anormal
- Función hepática anormal
- Nivel de EPO endógena sérica > 500 mU/ml en la selección
- Positividad conocida para el virus de la inmunodeficiencia humana (VIH) o diagnóstico de síndrome de inmunodeficiencia adquirida (SIDA), positivo para el antígeno de superficie de la hepatitis B, o seropositivo para el virus de la hepatitis C.
- Sujetos con abuso activo de etanol, según lo juzgue el investigador.
Que estén actualmente incluidos en otro estudio de investigación de fármaco o producto sanitario, o menos de 30 días desde la finalización de otros estudios de investigación de fármaco o producto sanitario, o que estén recibiendo otros agentes en investigación.
- Sujetos mujeres que no deseen utilizar medios anticonceptivos altamente eficaces durante el tratamiento y durante al menos 1 mes después de la finalización del tratamiento.
- Mujeres que estén embarazadas o que tengan pensado quedar embarazadas dentro del mes siguiente al final del tratamiento.
- Sujetos que tengan conocida sensibilidad a cualquiera de los productos a ser administrados en la posología.
- Sujetos que hayan sido aleatorizados previamente en este estudio.
- Sujetos que no vayan a estar disponibles para las visitas del estudio que requiere el protocolo, según sea el conocimiento del sujeto y del investigador.
- Sujetos que tengan cualquier trastorno, que, según la opinión del investigador, pueda comprometer la capacidad del sujeto de otorgar consentimiento informado por escrito y/o de cumplir con todos los procedimientos del estudio requeridos.
- Antecedentes confirmados de actividad de anticuerpos neutralizante para rHuEpo o Darbepoetin alfa.
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E.5 End points |
E.5.1 | Primary end point(s) |
Proportion of subjects achieving an IWG erythroid response during the double-blind treatment period. IWG erythroid response for non-transfusion dependent subjects is defined as achieving an initial ≥ 1.5 g/dL increase from baseline in haemoglobin level and sustaining an average rise of ≥ 1.5 g/dL in a rolling 56- consecutive day period in the absence RBC transfusion. IWG erythroid response will be determined based on central laboratory haemoglobin values. |
proporción de sujetos que alcanzan una respuesta eritroide del IWG durante el periodo de tratamiento con doble ciego.
La respuesta eritroide del IWG para sujetos no dependientes de transfusión se define como alcanzar un aumento inicial de ≥ 1,5 g/dl desde el inicio en el nivel de hemoglobina y mantener un aumento promedio de ≥ 1,5 g/dl en un periodo consecutivo de 56 días con ausencia de transfusiones de eritrocitos.
La respuesta eritroide del IWG se determinará según los valores de hemoglobina del laboratorio central.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Incidence of at least one RBC transfusion from week 5 to the end of the double-blind treatment period (EOTP) |
Incidencia de al menos 1 transfusión de eritrocitos desde la semana 5 hasta la finalización del periodo de tratamiento doble ciego. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 50 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial 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
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LVLS |
última visita del último sujeto incluido en el ensayo |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |