E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute myeloid leukemia |
Leucemia mieloide aguda |
|
E.1.1.1 | Medical condition in easily understood language |
Blood cancer |
Cáncer de sangre |
|
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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10024346 |
E.1.2 | Term | Leukemia myeloblastic acute |
E.1.2 | System Organ Class | 100000004864 |
|
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 |
Safety run-in: To assess the safety of i.v. teicoplanin prophylaxis three times per week with a two to three days interval in children with newly-diagnosed AML. A patient will be considered evaluable for safety if they experience a DLT during a prophylactic cycle with teicoplanin or, in case no DLT occurs, if exposure to teicoplanin is either at least 2 consecutive weeks with at least 5 doses of teicoplanin or at least 3 weeks in total with at least 6 out of 9 doses of teicoplanin, or 8 out of 12 doses in case of 4 weeks, or 10 out of 15 doses in case of 5 weeks.
Randomized phase: To evaluate whether i.v. teicoplanin prophylaxis in children with newly-diagnosed AML decreases the occurrence of culture-proven BSIs with VGS during treatment. |
Estudio de seguridad: Evaluar la seguridad de la profilaxis con teicoplanina tres veces por semana con un intervalo de dos a tres días en niños con LMA recién diagnosticada. Un paciente se considerará evaluable para la seguridad si experimenta una DLT durante un ciclo profiláctico con teicoplanina o, en caso de que no se produzca ninguna DLT, si la exposición a teicoplanina es de al menos 2 semanas consecutivas con al menos 5 dosis de teicoplanina o de al menos 3 semanas en total con al menos 6 de 9 dosis de teicoplanina, u 8 de 12 dosis en caso de 4 semanas, o 10 de 15 dosis en caso de 5 semanas.
Fase aleatoria: Evaluar si la profilaxis con teicoplanina en niños con LMA recién diagnosticada disminuye la aparición de ISB probadas por cultivo con VGS durante el tratamiento. |
|
E.2.2 | Secondary objectives of the trial |
Safety run-in: To (preliminary) characterize the PK parameters of teicoplanin in children with newly-diagnosed AML.
Randomized controlled trial: Evaluate whether i.v. teicoplanin prophylaxis decreases the occurrence of any culture-proven bacterial BSI; assess the impact of teicoplanin prophylaxis on the number of intensive care admissions; the frequency of infectious-related morbidity and mortality; evaluate whether i.v. teicoplanin prophylaxis affects neutrophil recovery time; development of teicoplanin-related bacterial resistance; The safety and AEs; To study if there is a confounding effect of the use of other antibiotics (e.g., fluoroquinolones) on the occurrence of culture-proven (VGS) bacterial BSIs; To assess PK parameters and construct a population PK model; To study the potential effect of co-variables on teicoplanin clearance; associations between serum levels of teicoplanin and the occurrence of culture-proven (VGS) bacterial BSIs. To describe the CIR, EFS and OS. |
Estudio de seguridad: Caracterizar los parámetros PK de teicoplanina en niños con LMA recién diagnosticada.
Ensayo controlado aleatorio: Evaluar si la profilaxis con teicoplanina disminuye la aparición de cualquier ISB bacteriana probada por cultivo; evaluar el impacto de la teicoplanina en el número de ingresos en cuidados intensivos; la frecuencia de morbilidad y mortalidad relacionadas con la infección; evaluar si la teicoplanina afecta al tiempo de recuperación de los neutrófilos; el desarrollo de la resistencia bacteriana relacionada con la teicoplanina; la seguridad y los EA; estudiar si existe un efecto de confusión del uso de otros antibióticos (p. ej, evaluar los parámetros PK y construir un modelo PK poblacional; estudiar el efecto potencial de las covariables sobre el aclaramiento de teicoplanina; asociaciones entre los niveles séricos de teicoplanina y la aparición de infecciones bacterianas (VGS) probadas por cultivo. Describir el CIR, la EFS y la OS. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Newly diagnosed with AML Being registered and starting treatment according to the NOPHO-DBH AML 2012 study protocol, or a consecutive protocol Age 0-19 years Written informed consent by the patient and/or legal guardians (whatever applicable according to the patients age) |
Recién diagnosticado de LMA Estar registrado e iniciar el tratamiento según el protocolo del estudio NOPHO-DBH AML 2012, o un protocolo consecutivo Edad de 0 a 19 años Consentimiento informado por escrito del paciente y/o de los tutores legales (lo que corresponda según la edad del paciente) |
|
E.4 | Principal exclusion criteria |
Acute promyelocytic leukemia Secondary AML Down Syndrome Preexisting primary immunodeficiency Patients who receive regular antibiotic prophylaxis against Gram-positive bacteria for other conditions than leukemia-related Patients with a history of a severe allergic reaction (CTCAE grade ≥3) to teicoplanin and/or vancomycin Patients with an eGFR of <30 ml/min/1.73m2 at the start of the study Patients with a history of severe impaired hearing (CTCAE grade ≥3) Pregnant or breast-feeding patients |
Leucemia promielocítica aguda LMA secundaria Síndrome de Down Inmunodeficiencia primaria preexistente Pacientes que reciben regularmente profilaxis antibiótica contra bacterias Gram-positivas por otras afecciones no relacionadas con la leucemia Pacientes con antecedentes de reacción alérgica grave (CTCAE grado ≥3) a teicoplanina y/o vancomicina Pacientes con un FGe de <30 ml/min/1,73m2 al inicio del estudio Pacientes con antecedentes de alteraciones auditivas graves (CTCAE grado ≥3) Pacientes embarazadas o en periodo de lactancia |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Safety run-in: The number of DLTs observed
Randomized controlled trial: The (first) occurrence of culture-proven BSIs with VGS during initial AML treatment; Date(s) of BSI(s) with VGS |
Prueba de seguridad: El número de DLTs observados
Ensayo controlado aleatorio: La (primera) aparición de BSIs probadas con VGS durante el tratamiento inicial de la LMA; Fecha(s) de la(s) ISB con VGS |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
During and after the safety run-in During the randomized controlled trial |
Durante y después del ensayo de seguridad Durante el ensayo controlado aleatorio |
|
E.5.2 | Secondary end point(s) |
Safety run-in: -Css,max -Css,min -Tss,max -Area under the curve -Clearance (inter-compartmental, total, renal fraction) -Volume of distribution (central and peripheral)
Randomized controlled trial: 1. The number of BSIs with culture-proven bacteria 2. Results of all positive blood cultures 3. Infection-related (pediatric) intensive care admissions; 4. The number of episodes/admissions with (neutropenic) fever; days with fever (with or without neutropenia), days with FN, Days with neurtopenia 5. Infection-free survival time, i.e., time from diagnosis till first culture-proven BSI; 6. Infection-related mortality; 7. Number of days until neutrophil recovery (ANC of ≥0.5 x109/L following the nadir); 8. Resistance patterns of pathogenic isolates from blood cultures; 9. Incidence of resistant bacteria in throat and rectal cultures, e.g.,; VRE 10. AEs of special interest; 11. Serious adverse events (SAEs); 12. Use of (other) antibiotics, antifungals and antivirals; 13. Serum creatinine levels 14. Serum teicoplanine levels 15. Cumulative incidence of relapse 16. Event-free survival 17. Overall survival |
Prueba de seguridad: -Css,max -Css,min -Tss,max -Área bajo la curva -Aclaramiento (intercompartimental, total, fracción renal) -Volumen de distribución (central y periférico)
Ensayo controlado aleatorio: 1. El número de ISB con bacterias probadas en cultivo 2. Resultados de todos los hemocultivos positivos 3. Ingresos en cuidados intensivos (pediátricos) relacionados con la infección; 4. El número de episodios/ingresos con fiebre (neutropénica); días con fiebre (con o sin neutropenia), días con FN, días con neutropenia 5. Tiempo de supervivencia libre de infección, es decir, tiempo desde el diagnóstico hasta la primera ISB probada por cultivo; 6. Mortalidad relacionada con la infección; 7. Número de días hasta la recuperación de neutrófilos (ANC de ≥0,5 x109/L tras el nadir); 8. Patrones de resistencia de los aislados patógenos de los hemocultivos; 9. Incidencia de bacterias resistentes en los cultivos de garganta y rectales, por ejemplo; VRE 10. EA de especial interés; 11. Acontecimientos adversos graves (SAE); 12. Uso de (otros) antibióticos, antifúngicos y antivirales; 13. Niveles de creatinina sérica 14. Niveles de teicoplanina en suero 15. Incidencia acumulada de recaídas 16. Supervivencia libre de eventos 17. Supervivencia global |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
During and after the safety run-in During the randomized controlled trial |
Durante y después del ensayo de seguridad Durante el ensayo controlado aleatorio |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
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 | 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 | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Atención estándar, pero sin profilaxis con teicoplanina |
Standard of care, but no teicoplanin prophylaxis |
|
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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 22 |
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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
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 | 6 |