| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Febrile neutrophenia in oncohematological pediatric patients. |
| Pacientes oncohematológicos pediátricos con neutropenia febril |
|
| E.1.1.1 | Medical condition in easily understood language |
| Febrile neutrophenia in oncohematological pediatric patients. |
| Pacientes oncohematológicos pediátricos con neutropenia febril |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10016288 |
| E.1.2 | Term | Febrile neutropenia |
| 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 evaluate safety of antibiotic withholding in pediatric cancer patients with FN with negative bacterial cultures at 48-72 hours after the onset of fever, absence of demonstrated bacterial infection, good clinical evolution (fever resolution and clinical stability) and PCT < 0,5ng/ml (experimental group), compared to classical strategy (control group), with regards to adverse events attributed to infection (death, PICU admission, sepsis, microbiology defined infection, radiologically confirmed pneumonia). |
| Evaluar la seguridad de la retirada precoz de antibióticos en el paciente pediátrico hematoncológico con neutropenia febril (< 500 neutrófilos/mm3) con ausencia de infección bacteriana demostrada, buena evolución clínica y valores bajos de biomarcadores (PCR < 5 mg/dl, PCT <0,5 ng/ml) (grupo experimental), comparado con la estrategia clásica (grupo control) en lo que respecta a acontecimientos adversos atribuibles a infección bacteriana (muerte, ingreso en UCIP, sepsis, infección definida clínica y/o microbiológicamente, neumonía confirmada radiológicamente). |
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate efficacy of antibiotic withholding as described previously, with regards to days of fever and total days of antibiotics.
2. To evaluate days of antibiotic reduction in the experimental group.
3. To evaluate reduction of adverse effects of prolonged antibiotic therapy in the experimental group.
4. To retrospectively evaluate the utility of biomarkers to better predict invasive bacterial infection at the fever onset and 48-72 hours after.
5. To validate a risk stratification score in our population. |
1. Evaluar la eficacia de la intervención del estudio, en lo que respecta a días de fiebre y total de días de antibiótico.
2. Evaluar la reducción de días de antibiótico en el grupo experimental.
3. Evaluar la reducción de efectos adversos de antibioterapia prolongada en el grupo experimental.
4. Evaluar la utilidad de los biomarcadores para predecir mejor la infección bacteriana invasiva al ingreso y a las 48-72 horas del inicio de la fiebre.
5. Validar un sistema de estratificación de riesgo adaptado a nuestro centro para esta población. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Female and male outpatients ≤18 years with haematological or solid malignancies.
- Admission due to FN (defined as an axillary temperature >38.3°C or two consecutive readings of >38.0°C for 1 hour and an absolute neutrophil count <0.5 neutrophils/mm3, or expected to fall below 0.5 neutrophils/mm3 during the next 48 hours).
- Antibiotic treatment initiated in the current FN episode (prior standard antimicrobial prophylaxis will be accepted).
- Low risk of invasive bacterial infection at admission:
o None of the following: serum level of CRP ≥ 9 mg/dl, hypotension, relapse of leukemia as type of cancer, platelet count ≤50,000 platelets/mm3, initiation of fever less than 7 days from last chemotherapy). Platelet count ≤50,000 platelets/mm3 or initiation of fever less than 7 days from the last chemotherapy alone will be accepted.
- Absence of a demonstrated bacterial infection at 48h-72 hours after admission (positive culture from a sterile site, clinically diagnosed infection or radiologically confirmed pneumonia).
- Good clinical evolution at 48-72 hours after admission (afebrile >24h (temperature ≤38ºC), haemodinamic stability, stable pediatric assessment triangle).
- CRP ≤ 5 mg/dl and PCT ≤ 0.5 ng/dl at 48-72 hours after admission.
- ANC < 0.5 neutrophils/mm3 at 48-72 hours after admission.
- Patient/parent(s)/legal representative(s) must possess writing and reading abilities sufficient to comprehend the study.
- Patient/parent(s)/legal representative(s) is considered reliable and capable of adhering to the protocol. |
- Pacientes de sexo femenino y masculino ≤18 años afectos de neoplasias hematológicas o sólidas.
- Neutropenia febril (NF) como diagnóstico principal al ingreso, definida como una única medición de temperatura axilar >38.3°C o dos mediciones separadas por una hora >38.0°C en un paciente con un recuento absoluto de neutrófilos < 500 neutrófilos/mm3, o que se espera que desciendan por debajo de ese valor durante las próximas 48 horas.
- Tratamiento antibiótico iniciado en el episodio actual de NF (se aceptarán las profilaxis antimicrobianas habituales).
- Bajo riesgo de infección bacteriana invasiva al ingreso:
o Ninguno de los siguientes: PCR ≥ 9 mg/dl, hipotensión, recaída de leucemia como enfermedad de base, recuento plaquetar ≤50,000 plaquetas/mm3, inicio de fiebre menos de 7 días tras la última quimioterapia. Se aceptará la presencia aislada de recuento plaquetar ≤50,000 platequetas/mm3 o inicio de la fiebre menos de 7 días tras la última quimioterapia.
- Ausencia de infección bacteriana demostrada a las 48-72 horas del ingreso, definida como cultivo bacteriano positivo, infección diagnosticada clínicamente o neumonía confirmada radiológicamente.
- Buena evolución clínica a las 48-72 horas del ingreso, definida como afebril >24h (temperatura axilar <38ºC), estable hemodinámicamente y con un triángulo de evaluación pediátrica estable.
- PCR ≤ 5 mg/dl y PCT <0,5 ng/dl a las 48-72 horas del ingreso.
- ANC < 500 neutrófilos/mm3 a las 48-72 horas del ingreso.
- El paciente/padre(s)/representante(s) legal(es) deberán poseer habilidades de lectura y escritura suficientes para entender y dar su conformidad para participar en el estudio.
- El paciente/padre(s)/representante(s) legal(es) deberán considerarse fiables y capaces de adherirse al protocolo. |
|
| E.4 | Principal exclusion criteria |
- Patient that has undergone stem cell transplantation
- Patient with acute myeloblastic leukemia or Philadelphia-positive acute lymphoblastic leukemia
- Admission due to other cause different from FN.
- Antibiotic treatment prior to admission other than the usual antimicrobial prophylaxis.
- Empiric antibiotic therapy not in accordance with internal protocol.
- Confirmed allergy to betalactams.
- Bad clinical evolution in the first 12 hours after admission (haemodinamic instability, admission to PICU, death).
- Actively participating in the study at the beginning of the current FN episode.
- Concurrent participation in any other clinical trial.
- Any condition for which, in opinion of the investigator, participation would not be in the best interest of the patient or that could prevent, limit or confound the protocol-specified assessments.
- Female subjects who are pregnant or breast-feeding
- Signed informed consent by patient/parent(s)/legal representative(s). |
- Paciente sometido a trasplante de progenitores hematopoyéticos.
- Paciente afecto de leucemia aguda mieloblástica o leucemia aguda linfoblástica Philadelphia positivo.
- Ingreso por otro motivo diferente de neutropenia febril.
- Tratamiento antibiótico en el momento del ingreso diferente al usado de forma profiláctica.
- Tratamiento antibiótico empírico diferente al indicado en el protocolo interno.
- Alergia confirmada a betalactámicos.
- Paciente con mala evolución clínica en las primeras 12 horas (inestabilidad hemodinámica, ingreso en UCIP, muerte).
- Participación activa en el mismo estudio al inicio del episodio actual de NF.
- Participación activa en otro ensayo clínico.
- Cualquier condición que, en opinión del investigador, cause que la participación en el estudio no sea adecuada para el paciente o que podría limitar, impedir o confundir las valoraciones previstas en el protocolo.
- Mujeres embarazadas o en periodo de lactancia
- Consentimiento informado firmado por el paciente/padre(s)/representante(s) legal(es). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Adverse events attributed to infection (death, PICU admission, sepsis, microbiology and/or clinically defined infection, radiologically confirmed pneumonia). |
| Acontecimientos adversos atribuibles a infección bacteriana: muerte, ingreso en UCIP, sepsis, infección definida clínica y/o microbiológicamente, neumonía confirmada radiológicamente. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- Days of fever.
- Days of and type of antimicrobials.
- Days of neutropenia.
- Patient characteristics: age, gender, origin, underlying disease, treatment phase, days from last chemotherapy, catheter type, clinical features, physical examination, hours of fever at admission, vital signs, PICU admission, risk score.
- Analytical values (at admission, at 48-72 hours and at 28 days): hematology panel, serum chemistry panel (appendix), PCR, PCT.
- IL-8 (at admission and at 48-72 hours).
- Microbiological results: blood and urine cultures. Others if performed (nasopharyngeal swab, cerebrospinal fluid culture, etc).
- Imaging results: X-ray, CT scan, MRI, US, others.
- Incidence and severity of adverse effects.
- Concomitant medication. |
- Días de fiebre.
- Días y tipo de antibióticos administrados.
- Días de neutropenia.
- Características del paciente: edad, sexo, origen, enfermedad de base, fase de tratamiento, días desde el último ciclo de quimioterapia, tipo de catéter, signos y síntomas clínicos, examen físico, constantes vitales, horas de fiebre al ingreso, ingreso en UCIP, clasificación de riesgo.
- Resultados analíticos (al ingreso, a las 48-72 horas y a los 28 días): hematología, bioquímica sérica (anexos), PCR, PCT,
- Resultado de la determinación de IL-8 (al ingreso y a las 48-72 horas).
- Resultados microbiológicos: hemocultivo, urocultivo, otros si se realizan (aspirado nasofaríngeo, cultivo de líquido cefalorraquídeo, etc.).
- Pruebas de imagen: radiografía, ecografía, TC, otros.
- Incidencia y gravedad de efectos adversos.
- Medicación concomitante administrada. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
48 and 72 hours
7 and 14 days |
48 y 72 horas
7 y 14 días |
|
| 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 | 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) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Práctica Clínica Habitual |
| Standar of Care |
|
| 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 | No |
| 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 | 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
|
| LVLS |
| Última visita último paciente |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 24 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 24 |
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