| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pediatric patients with previously treated chronic immune (idiopathic) thrombocytopenic purpura (ITP). |
| Púrpura Trombocitopénica Inmune (Idiopática) Crónica en pacientes pediátricos previamente tratados. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Childhood chronic immune thrombocytopenic purpura, ITP, a blood disorder of low platelet counts that can lead to bruising easily, bleeding gums, and/or bleeding inside the body. |
| Púrpura trombocitopénica inmune crónica, en niños, es un trastorno sanguíneo con bajo número de plaquetas que puede producir moratones, sangrado de encías o sangrado en el interior del cuerpo. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10021245 |
| E.1.2 | Term | Idiopathic thrombocytopenic purpura |
| E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
|
| 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 assess the efficacy of eltrombopag, relative to placebo, in achieving platelet counts of >= 50 Gi/L, when administered to pediatric subjects with previously treated chronic ITP during the first 12 weeks of Part 1, the randomized treatment period. |
| Evaluar la eficacia de eltrombopag, respecto a placebo, para alcanzar recuentos de plaquetas >=50 Gi/L cuando se administra a sujetos pediátricos con PTI crónica previamente tratada durante las 12 semanas primeras de la Parte 1, el periodo de tratamiento aleatorizado. |
|
| E.2.2 | Secondary objectives of the trial |
To describe the efficacy of eltrombopag in achieving platelet counts >= 50 Gi/L when administered to pediatric subjects with previously treated chronic ITP.
To assess the efficacy of eltrombopag in achieving sustained platelet counts >= 50 Gi/L when administered to pediatric subjects with previously treated chronic ITP.
To describe the effect of eltrombopag on reduction and/or interruption of concomitant ITP therapies, when administered for 24 weeks to pediatric subjects with previously treated chronic ITP.
To describe the effect of eltrombopag on the need for rescue ITP medication when administered to pediatric subjects with previously treated chronic ITP.
To assess the efficacy of eltrombopag in decreasing the incidence and severity of bleeding symptoms when administered in pediatric subjects with previously treated chronic. Please refer to the protocol for the remaining objectives P12. |
Describir la eficacia de eltrombopag, respecto a placebo, para alcanzar recuentos de plaquetas >=50 Gi/L cuando se administra a sujetos pediátricos con PTI crónica previamente tratados.
Evaluar la eficacia de eltrombopag para alcanzar recuentos de plaquetas mantenidos >=50 Gi/L cuando se administra a sujetos pediátricos con PTI crónica previamente tratados.
Describir el efecto de eltrombopag sobre la reducción y/o interrupción de terapias concomitantes para la PTI, cuando se administra durante 24 semanas a sujetos pediátricos con PTI crónica previamente tratados.
Describir el efecto de eltrombopag sobre la necesidad de medicación de rescate para la PTI cuando se administra a sujetos pediátricos con PTI crónica previamente tratados.
Para el resto de objetivos, por favor véase la página 12 del Protocolo. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Written informed consent must be obtained from the subject's guardian and accompanying informed assent from the subject (for children over 6 years old).
2. Subjects must be between 1 year and <18 years of age at Day 1.
3. Subjects will have a confirmed diagnosis of chronic ITP for at least 1 year, at screening, according to the guidelines published in the International Working Group Report [Rodeghiero, 2009].
4. A peripheral blood smear or bone marrow examination will support the diagnosis of ITP with no evidence of other causes of thrombocytopenia.
5. Subjects must be refractory or have relapsed after at least one prior ITP therapy, or subjects must be unable, for a medical reason, to continue other ITP treatments.
6. Subjects must have a Day 1 (or within 48 hours prior) platelet count <30 Gi/L.
7. Previous therapy for ITP with immunoglobulins (IVIg and anti-D) must have been completed at least 2 weeks prior to Day 1, or these therapies must have been completed at least 1 week prior to Day 1 and have been clearly ineffective.
8. Previous treatment for ITP with splenectomy, rituximab and cyclophosphamide must have been completed at least 4 weeks prior to Day 1.
9. Subjects treated with concomitant ITP medication (e.g. corticosteroids or azathioprine) must be receiving a dose that has been stable for at least 4 weeks prior to Day 1.
10. Subjects must have a complete blood count (CBC) not suggestive of another hematological disorder.
11. Subjects must have the following laboratory results:
? prothrombin time international normalized ratio (INR) and activated partial thromboplastin time (aPTT) within 80 to 120% of the normal range.
? clinical chemistries that do NOT exceed the upper limit of normal (ULN) reference range by more than 20% for the following: creatinine, ALT, AST, total bilirubin, and alkaline phosphatase.
? total albumin that is not below the lower limit of normal (LLN) by more than 10%.
12. Female subjects of child-bearing potential (after menarche) must:
? have a negative pregnancy test within 24 hours of first dose of study treatment,
? agree and be able to provide a blood or urine specimen for pregnancy testing during the study,
? agree to use effective contraception, as defined in Section 7.3.3, during the study and for 28 days following the last dose of study treatment, and
? not be lactating.
13. Male subjects with a female partner of childbearing potential must agree to use effective contraception as described in Section 7.3.3 from 2 weeks prior to administration of the first dose of study treatment until 3 months after the last dose of study treatment.
14. In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category. |
1. Se ha obtenido el consentimiento informado del tutor del sujeto y el asentimiento informado del sujeto (en los niños mayores de 6 años).
2. Los sujetos deben tener una edad comprendida entre 1 año y <18 años el Día 1.
3. Los sujetos deben tener un diagnóstico confirmado de PTI crónica de al menos 1 año de evolución en la visita de selección, de acuerdo con las directrices publicadas en el International Working Group Report [Rodeghiero, 2009].
4. Un frotis de sangre periférica o un examen de médula ósea apoyará el diagnóstico de PTI sin evidencia de otras causas de trombocitopenia.
5. Los sujetos deben tener una enfermedad refractaria al tratamiento o que haya recidivado después de al menos un tratamiento anterior para la PTI, o los sujetos deben ser incapaces, por razones médicas, de continuar otros tratamientos para la PTI.
6. El recuento de plaquetas el Día 1 (o en las 48 horas anteriores) debe ser <30 Gi/L.
7. La terapia previa para la PTI con inmunoglobulinas (IVIg y anti-D) debe haberse completado al menos 2 semanas antes del Día 1, o estas terapias deben haberse completado al menos 1 semanas antes del Día 1 y haber sido claramente ineficaces.
8. El tratamiento previo de la PTI con esplenectomía, rituximab y ciclofosfamida debe haberse completado al menos 4 semanas antes del Día 1.
9. Los sujetos tratados con mediación concomitante para la PTI (por ejemplo, corticosteroides o azatioprina) deben estar recibiendo una dosis que haya permanecido estable al menos durante 4 semanas antes del Día 1.
10. Los sujetos deben tener un recuento sanguíneo completo que no indique ningún otro trastorno hematológico.
11. Los sujetos deben tener los siguientes resultados de laboratorio:
- Tiempo de protrombina, international normalized ratio (INR) y tiempo de tromboplastina parcial activada (TTPa) dentro del 80-120% del rango normal.
- Parámetros bioquímicos que NO estén más de un 20% por encima del límite superior normal (LSN) del rango de referencia para los siguientes: creatinina, ALT, AST, bilirrubina total y fosfatasa alcalina.
- Albúmina total que no esté más de un 10% por debajo del límite inferior normal (LIN).
12. Las mujeres potencialmente fértiles (después de la menarquia) deben:
- tener una prueba de embarazo negativa en las 24 horas anteriores a la primera dosis de tratamiento del estudio
- estar de acuerdo y ser capaces de proporcionar una muestra de sangre u orina para la prueba de embarazo durante el estudio
- estar de acuerdo en utilizar un método anticonceptivo efectivo, como se define en la Sección 7.3.3, durante el estudio y durante 28 días después de la última dosis de tratamiento del estudio, y
- no estar el periodo de lactancia.
13. Los varones con una pareja femenina potencialmente fértil deben estar de acuerdo en utilizar un método anticonceptivo efectivo como se describe en la Sección 7.3.3 desde 2 semanas antes de la administración de la primera dosis de tratamiento del estudio hasta 3 meses después de la última dosis de tratamiento del estudio.
14. En Francia, un sujeto sólo será elegible para participar en el estudio si está afiliado o es beneficiario de la seguridad social. |
|
| E.4 | Principal exclusion criteria |
1. Subjects with any clinically relevant abnormality, other than ITP, identified on the screening examination or any other medical condition or circumstance, which in the opinion of the investigator makes the subject unsuitable for participation in the study or suggests another primary diagnosis (e.g. Thrombocytopenia is secondary to another disease).
2. Subjects with concurrent or past malignant disease, including myeloproliferative disorder.
3. Subjects expected not to be suitable for continuation of their current therapy for at least 13 additional weeks.
4. Subjects with a history of platelet agglutination abnormality that prevents reliable measurement of platelet counts.
5. Subjects with a diagnosis of secondary immune thrombocytopenia, including those with laboratory or clinical evidence of HIV infection, anti-phospholipid antibody syndrome, chronic hepatitis B infection, hepatitis c virus infection, or any evidence of active hepatitis at the time of subject screening.
6. Subjects with Evans syndrome (autoimmune thrombocytopenia and autoimmune hemolysis).
7. Subjects with known inherited thrombocytopenia (e.g. MYH9 disorders).
8. Subjects treated with any medication that affects platelet function (including but not limited to aspirin, clopidogrel and/or NSAIDS) or anti-coagulants for >3 consecutive days within 2 weeks of Day 1, or subjects treated with any prohibited medication as described in Section 6.2.
9. Subjects who have received treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) preceding Day 1.
10. Subjects who have previously received eltrombopag or any other thrombopoietin receptor agonist.
11. Any subject considered to be a child in care, defined as one who has been placed under the control or protection of an agency, organization, institution or entity by the courts, the government or a government body, acting in accordance with powers conferred on them by law or regulation. This can include a child cared for by foster parents or living in a care home or institution, provided that the arrangement falls within the definition above. The definition of a child in care does not include a child who is adopted or who has an appointed legal guardian.
12. Subjects who have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to eltrombopag or excipients that contraindicates their participation.
13. Any serious and/or unstable pre-existing medical, psychiatric disorder, or other conditions that could interfere with the subject?s safety or compliance to the study procedures. |
1. Sujetos con cualquier anomalía clínicamente relevante, distinta de la PTI, identificada en la selección, o cualquier otro trastorno o circunstancia médica que, a juicio del investigador, haga que el sujeto sea inadecuado para participar en el estudio o indique otro diagnóstico primario (por ejemplo, trombocitopenia secundaria a otra enfermedad).
2. Sujetos con cáncer en la actualidad o en el pasado, incluido el síndrome mieloproliferativo.
3. Sujetos que se considere que no están capacitados para continuar su tratamiento actual al menos durante 13 semanas más.
4. Sujetos con historia de anomalía de aglutinación de las plaquetas que impida la medición fiable del recuento de plaquetas.
5. Sujetos con diagnóstico de trombocitopenia inmune secundaria, incluidos aquellos con evidencia clínica o de laboratorio de infección por VIH, síndrome de anticuerpos anti-fosfolípidos, hepatitis B crónica, infección por el virus de la hepatitis C, o cualquier evidencia de hepatitis activa en el momento de la selección.
6. Sujetos con síndrome de Evans (trombocitopenia autoinmune y hemolisis autoinmune).
7. Sujetos con trombocitopenia hereditaria conocida (por ejemplo, trastornos MYH9).
8. Sujetos tratados con cualquier medicación que afecte a la función plaquetaria (incluidos pero no limitados a aspirina, clopidogrel y/o AINEs) o anticoagulantes durante >3 días consecutivos en las 2 semanas anteriores al Día 1, o sujetos tratados con cualquiera de las medicaciones prohibidas que se describen en la Sección 6.2.
9. Sujetos que hayan recibido tratamiento con un fármaco en investigación en los 30 días o 5 semividas (lo que sea más largo) anteriores al Día 1.
10. Sujetos que hayan recibido previamente eltrombopag o cualquier otro agonista de los receptores de trombopoyetina.
11. Cualquier sujeto que se considere un niño bajo custodia, definido como aquel que se ha dejado por orden judicial bajo el control o protección de una organización, institución o entidad. Esto puede incluir niños cuidados por padres de acogida o que viven en una institución, siempre que la configuración entre dentro de la definición anterior. La definición de niño custodiado no incluye a los niños adoptados o que tienen un tutor legal.
12. Sujetos con hipersensibilidad inmediata o tardía o idiosincrasia conocida a fármacos químicamente relacionados con eltrombopag o sus excipientes, que contraindique su participación.
13. Cualquier trastorno preexiste médico, psiquiátrico o de otra naturaleza, grave y/o inestable, que pueda interferir con la seguridad o el cumplimiento del sujeto con los procedimientos del estudio. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The odds of achieving platelet counts >= 50 Gi/L during the first 12 weeks of Part 1, the randomized treatment period, for subjects receiving eltrombopag relative to placebo. |
| La variable primaria es la posibilidad de alcanzar recuentos de plaquetas >=50 Gi/L durante las 12 semanas primeras de la Parte 1, el periodo de tratamiento aleatorizado, en los sujetos que reciban eltrombopag frente a los que reciban placebo. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Primary endpoint will be based on platelet counts obtained through the first 12 weeks of Part 1. |
| La variable primaria se basará en los recuentos de plaquetas obtenidos durante las primeras 12 semanas de la Parte 1. |
|
| E.5.2 | Secondary end point(s) |
The proportion of subjects receiving eltrombopag, compared to placebo, who achieve platelet counts >= 50
Gi/L for at least 6 out of 8 weeks, between weeks 5-12 of Part 1.
Weighted mean platelet change (area under the platelet-time curve divided by duration), for subjects receiving eltrombopag relative to placebo, from baseline to Week 12 of Part 1.
The proportion of subjects receiving eltrombopag, compared to placebo, who achieve platelet counts >= 50 Gi/L at any time during the first 6 weeks of Part 1.
The proportion of subjects receiving eltrombopag, compared to placebo, who achieve platelet counts >= 50 Gi/L at any time during the first 12 weeks of Part 1.
The proportion of subjects achieving platelet counts >= 50 Gi/L at any time during Part 2.
Maximum period of time with platelet counts continuously >= 50 Gi/L for subjects receiving eltrombopag relative to placebo during the first 12 weeks of Part 1.
The proportion of weeks in which subjects achieve platelet counts >= 50 Gi/L, between weeks 4-24 of Part 2.
Maximum period of time with platelet counts continuously >= 50 Gi/L during Part 2.
The proportion of subjects who reduced or discontinued baseline concomitant ITP medications during Part 2.
The proportion of subjects receiving eltrombopag, relative to placebo, who required protocol-defined rescue treatment during Part 1.
The proportion of subjects who required protocol-defined rescue treatment during Part 2.
Incidence and severity of symptoms associated with ITP, including bleeding, bruising and petechiae, measured using the World Health Organization (WHO) Bleeding Scale for subjects receiving eltrombopag relative to placebo, during Part 1.
Incidence and severity of symptoms associated with ITP, including bleeding, bruising and petechiae, measured using the WHO Bleeding Scale during Part 2.
Safety and tolerability parameters including blood pressure and heart rate, ophthalmic examinations, clinical laboratory assessments and frequency of all adverse events, categorized using Common Terminology Criteria for Adverse Events (CTCAE) v4 toxicity grades.
PK data collected in this study will be included in a population PK analysis in order to estimate primary model-based PK parameters such as CL/F, Q/F, Vc/F, Vp/F, and ka and the influence of potential covariates on these parameters. |
La proporción de sujetos que reciben eltrombopag, en comparación con placebo, que alcanzan recuentos de plaquetas >=50 Gi/L durante al menos 6 de cada 8 semanas, entre las semanas 5-12 de la Parte 1.
- Media ponderada del cambio plaquetario (área bajo la curva plaquetas-tiempo dividida por la duración), en los sujetos tratados con eltrombopag respecto a placebo, desde la evaluación basal hasta la Semana 12 de la Parte 1.
- Proporción de sujetos de los que reciben eltrombopag, en comparación con placebo, que alcanzan recuentos de plaquetas >=50 Gi/L en cualquier momento durante las 6 primeras semanas de la Parte 1.
- Proporción de sujetos de los que reciben eltrombopag, en comparación con placebo, que alcanzan recuentos de plaquetas >=50 Gi/L en cualquier momento durante las 12 primeras semanas de la Parte 1.
- Proporción de sujetos que alcanzan recuentos de plaquetas >=50 Gi/L en cualquier momento durante la Parte 2
- Periodo máximo de tiempo con recuentos de plaquetas sostenidos >=50 Gi/L en los sujetos tratados con eltrombopag respecto a placebo, durante las 12 primeras semanas de la Parte 1.
- Proporción de semanas en las que los sujetos alcanzan recuentos de plaquetas >=50 Gi/L, entre las semanas 4-24 de la Parte 2.
- Periodo máximo de tiempo con recuentos de plaquetas sostenidos >=50 Gi/L durante la Parte 2.
- Proporción de sujetos que reducen o interrumpen las medicaciones basales concomitantes para la PTI durante la Parte 2.
- Proporción de sujetos que reciben eltrombopag, en comparación con placebo, que necesitan tratamiento de rescate definido por protocolo durante la Parte 1.
- Proporción de sujetos que necesitan tratamiento de rescate definido por protocolo durante la Parte 2.
- Incidencia y gravedad de los síntomas asociados a la PTI, que incluyen sangrados, hematomas y petequias, medidos utilizando la Escala de Sangrado de la Organización Mundial de la Salud (OMS) en los sujetos tratados con eltrombopag respecto a placebo, durante la Parte 1.
- Incidencia y gravedad de los síntomas asociados a la PTI, que incluyen sangrados, hematomas y petequias, medidos utilizando la Escala de Sangrado de la OMS durante la Parte 2. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Secondary endpoints span up to 13 weeks in Part 1 and up to 24 weeks in Part 2. |
| La variable secundaria se extiende hasta 13 semanas en la Parte 1 y hasta 24 semanas en la Parte 2. |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | 3 |
| 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 | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 27 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Chile |
| Czech Republic |
| Germany |
| Hong Kong |
| Israel |
| Italy |
| Poland |
| Russian Federation |
| Spain |
| Taiwan |
| Thailand |
| United Kingdom |
| United States |
|
| E.8.7 | Trial 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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