E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Idiopathic (Severe) Aplastic Anemia, a bone marrow failure syndrome which results in the normal hematopoietic tissue completely missing from the bone marrow, accounting for the subsequent pancytopenia. |
Anemia Idiopática aplástica severa, un síndrome de insuficiencia de la médula ósea que se traduce en el tejido hematopoyético normal, completamente ausente de la médula ósea, lo que representa la pancitopenia subsiguiente. |
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E.1.1.1 | Medical condition in easily understood language |
Severe aplastic anemia is an hematological disease of the bone marrow resulting in pancytopenia, a medical condition where there is a reduction in numbers of red-, white blood cells and platelets. |
Anemia aplástica severa es una enf. hematológica de la médula ósea que resulta en pancitopenia, una condición médica donde hay una reducción del número de células blancas en sangre, red y plaquetas |
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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 | 18.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10002967 |
E.1.2 | Term | Aplastic anaemia |
E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To investigate whether Eltrombopag added to standard immunosuppressive treatment increases the rate of early (at three months) complete response in untreated AA patient. |
Investigar si Eltrombopag añadió al tratamiento inmunosupresor estándar aumenta la tasa de temprana (a los tres meses) respuesta completa en AA paciente no tratado. |
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E.2.2 | Secondary objectives of the trial |
To investigate the impact of Eltrombopag added to standard treatment on all heamatology outcome measures, Quality of Life and safety/tolerability in untreated AA patients. |
Investigar el impacto de eltrombopag añadido al tratamiento estándar en todas las medidas de resultado heamatology, calidad de vida y la seguridad / tolerabilidad en pacientes no tratados AA. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Diagnosis of severe or very severe aplastic anemia, defined by
? At least two of the following:
? Absolute neutrophil counts <0.5 x 10(9)/L (severe) or
<0.2 x 10(9)/L (very severe)
? Platelet counts <20 x 10(9)/L
? Reticulocyte counts <60 x 10(9)/L
? Hypocellular bone marrow (<30% cellularity), without evidences of fibrosis or malignant cells
2.Age ? 15 years;
3.Written informed consent |
1.Diagnosis de la anemia aplástica grave o muy grave, definida por:
Al menos dos de los siguientes:
Recuento absoluto de neutrófilos <0,5 x 10 (9) / L (grave) o
<0,2 x 10 (9) / L (muy grave)
Los recuentos de plaquetas <20 x 10 (9) / L
El recuento de reticulocitos <60 x 10 (9) / L
Hipocelular médula ósea (<30% celularidad), sin evidencias de fibrosis o células malignas
2.Age: 15 años;
3.Written consentimiento informado |
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E.4 | Principal exclusion criteria |
1.Prior immunosuppressive therapy with ATG (horse of rabbit) or any other lymphocyte depleting agent (i.e., alemtuzumab)
2.Eligibility to a sibling allogeneic stem cell transplantation
3.Evidence of a myelodysplastic syndrome, defined by the presence of myelodysplastic features, excess of blasts or karyotypic abnormalities typical of MDS (according to revised WHO 2008
criteria) , as well as other primitive marrow disease. Patients with diagnosis of AA with cytogenetic abnormalities which are recurrent in MDS (according to revised WHO 2008 criteria) should be included in this category, and are not eligible for the study; patients with del(20q), +8 and ?Y are not included in this category, and thus are eligible for this study. The list of karyotypic abnormalities which qualifies for the diagnosis of MDS are listed in Appendix 1 of the protocol
4.History or clinical suspect of constitutional aplastic anemia (i.e. Fanconi Anemia with positive DEB/MMC test or Dyskeratosis Congenita)
5.History of malignant tumors with active disease within 5 years from enrollment and/or previous chemo-rediotherapy
6.Previous history of stem cell transplantation
7.Treatment with cyclosporin A <2 weeks before enrollment
8.CMV viremia, as defined by positive PCR or pp65 test
9.WHO performance status ?3
10.Pregnant or breast feeding patients
11.Patients with hepatic, renal or cardiac failure, or any other life-
threatening concurrent disease
12.Patients with HIV infection
13.Patients without social health care assistance
14.Participation in another clinical trial within 1 month before the start of this trial
15.Subjects with known hypersensitivity to any of the component medications |
1.Terapia inmunosupresora antes con ATG (caballo de conejo) o cualquier agente que agotan otra linfocitos (es decir, el alemtuzumab)
2.Eligibility a un hermano el trasplante alogénico de células madre
3.Evidence de un síndrome mielodisplásico, definido por la presencia de características mielodisplásicos, exceso de blastos o anormalidades cariotípicas típicos de MDS (de acuerdo con la OMS revisada 2008
criterios), así como otra enfermedad ósea primitiva. Los pacientes con diagnóstico de AA con anormalidades citogenéticas que son recurrentes en MDS (según criterios revisados de la OMS 2008) deben incluirse en esta categoría, y no son elegibles para el estudio; pacientes con del (20q), 8 y? Y no se incluyen en esta categoría, y por lo tanto son elegibles para este estudio. La lista de las anomalías del cariotipo que califica para el diagnóstico de MDS se enumeran en el Apéndice 1 del protocolo
4.History o sospecha clínica de la anemia aplásica constitucional (es decir, la Anemia de Fanconi con la prueba de MMC positivo DEB / o disqueratosis congénita)
5.History de tumores malignos con enfermedad activa dentro de los 5 años a partir de la matrícula y / o el anterior quimio-rediotherapy
Historia 6.Previous de trasplante de células madre
7.Treatment con ciclosporina A <2 semanas antes de la inscripción
Viremia 8.CMV, según lo definido por PCR positiva o prueba de pp65
Rendimiento 9.WHO estado? 3
10.Pregnant o pacientes en periodo de lactancia
11.Patients con insuficiencia hepática, renal o insuficiencia cardíaca o cualquier otra vida
enfermedades concurrentes mortal
12.Patients con la infección por VIH
13.Patients sin asistencia atención sociosanitaria
14.Participation en otro ensayo clínico en 1 mes antes del inicio de este ensayo
15.Subjects con hipersensibilidad conocida a cualquiera de los medicamentos de componentes |
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E.5 End points |
E.5.1 | Primary end point(s) |
Rate of Complete response (defined as Hb >10 g/dL, ANC > 1,000/?L and Plt >100,000 ?L) at 3 months since start of treatment in untreated severe AA patients. |
Tasa de respuesta completa (definida como Hb> 10 g / dl, RAN> 1.000 L /? Y Plt> 100 000? L) a los 3 meses desde el inicio del tratamiento en pacientes AA graves no tratados. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
For the main endpoint a valid response has to be measured between month 3 plus or minus 10 days; in case of more than one measurement available in this time period, the best response will be taken. |
Para el punto final principal de una respuesta válida tiene que medir entre 3 meses más o menos de 10 días; en el caso de más de una medición disponible en este período de tiempo, se tomará la mejor respuesta. |
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E.5.2 | Secondary end point(s) |
1.Time to first hematological response (complete or partial) described by a cumulative incidence curve
2.Time to best hematological response, described by a cumulative incidence curve
3.Time to complete response
4.Rates of hematological response (overall, complete, partial) at 6, 12, 18 and 24 months
5.Overall survival (OS) probability; OS is defined as time from treatment starting (day 1) to death, or last follow-up for patients alive
6.Event-free survival (EFS) probability;
7.Cumulative incidence of relapse, from first hematological response (complete or partial)
8.Cumulative incidence of clonal evolution : AML, MDS or karyotypic abnormalities
9.Cumulative incidence of PNH population occurrence and clinical hemolytic PNH occurrence
10.Cumulative incidence of discontinuation of immunosuppressive therapy
11.Rate of CsA-independent hematological response at 24 months
12.Need for transfusions (packed red cell units and platelet units) and number of transfusions required from treatment.
13.Need for any supportive care, including hospitalization
14.Quality of life (as assessed by the validated EORTC QLQ-C30 questionnaire)(changes over time and differences between treatment arms)
15.Safety and tolerability of the investigational treatment, including SAE |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
3, 6, 12, 18 and 24 months |
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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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
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) | Yes |
E.8.2.2 | Placebo | No |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 31 |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
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 | 5 |
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 |