E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Anakinra treatment is expected to reduce the early and long term mortality of patients with Kawasaki Disease (KD), by a rapid and sustained effect on vascular inflammation |
el tratamiento anakinra deberia reducir la mortalidad precoz y a largo plazo de los patientes afectados por la enfermedad de kawasaki, para un efecto importante y rapido en la inflamacion vascular. |
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E.1.1.1 | Medical condition in easily understood language |
Anakinra treatment is expected to reduce the early and long term mortality of patients with Kawasaki Disease (KD), by a rapid and sustained effect on vascular inflammation |
el tratamiento anakinra deberia reducir la mortalidad precoz y a largo plazo de los patientes afectados por la enfermedad de kawasaki, para un efecto importante y rapido en la inflamacion vascular. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10023320 |
E.1.2 | Term | Kawasaki's disease |
E.1.2 | System Organ Class | 10047065 - Vascular 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 |
Assess the efficacy of anakinra (IL-1R1receptor antagonist) in patients on fever with KD who fail to respond to one infusion of IVIg (standard treatment). |
Evaluar la eficacia de anakinra (antagonista del receptor R1 de IL-1) en pacientes febriles con EK que no respondieron a una infusión de IGIV (tratamiento standard). |
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E.2.2 | Secondary objectives of the trial |
-To assess the efficacy of anakinra on disease activity -To assess the efficacy of anakinra on coronary lesions (eg: dilatation and aneurysm) -To assess the efficacy of anakinra on inflammation -To assess the safety and tolerability of anakinra |
-Evaluar la eficacia de anakinra sobre la actividad de la enfermedad -Evaluar la eficacia de anakinra sobre las lesiones coronarias (p. ej.: dilatación y aneurisma) -Evaluar la eficacia de anakinra sobre la inflamación -Evaluar la seguridad y tolerancia de anakinra |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
-inflammatory biomarkers -gene expression profiling -endothelial cell activation markers -antibodies against anakinra |
-biomarcadores -inflamatorios -perfiles de la expresión de los genes -marcadores de activación de células endotheliales -anticuerpos contra anakinra |
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E.3 | Principal inclusion criteria |
1. Patient, male and female, ? 8 months of life and ? 18 years old,
2. Patient ? 10 kg
3. Patient with KD according to the American Heart Association definition for complete or incomplete KD. (Fever ? 5 days (or at least 3 days if KD with AHA criteria since the third day of fever) and ? 4 of 5 main clinical signs: modification of the extremities, polymorphic exanthema, bilateral bulbar not exudative conjunctivitis, erythema of the lips or oral cavity, and cervical lymph nodes usually unilateral > 1.5 cm in diameter. In the presence of less than 4 clinical criteria and 5 days of fever, the diagnosis of disease KD is proposed in case of coronary abnormalities (at least one dilated coronary artery with internal diameter ? 2,5 SD from the mean normalized for body surface area (Z score) as determined by echocardiography). For indicative purpose, in case of incomplete KD, other biological supportive criteria for incomplete KD can help to ensure the diagnosis: leucocytosis, elevated CRP, elevated ESR, anaemia, hyponatremia, elevated ASAT, ALAT and gGT, hyperlipidaemia.
4. Patient who failed to respond to standard therapy of KD: e.g. Persistence or recrudescence of fever ? 38°C, 48 hours after the infusion of 2g/kg of IV Ig, The interval may be reduced to 24h after the end of the infusion if the patient is still febrile 24h after the end of the infusion.
5. Patient, parents or legal guardian?s written informed consent is required
6. Patient with health insurance
7. Patient agrees to have effective contraception for the duration of participation in the research |
1. Paciente de sexo masculino o femenino, ? 8 meses y ? 18 años de edad.
2. Paciente ? 10 kg
3. Paciente con EK, de acuerdo con la definición de la American Heart Association para una EK completa o incompleta. (Fiebre ? 5 días o al menos 3 días si EK cumple criterios de la AHA desde el tercer día de fiebre) y ? 4 de los 5 signos clínicos principales: modificación de las extremidades, exantema polimórfico, conjuntivitis bilateral bulbar no exudativa, eritema de los labios o de la cavidad bucal, y nódulos linfáticos cervicales habitualmente unilaterales > 1.5 cm de diámetro. En presencia de menos de 4 de los criterios clínicos y de 5 días de fiebre, se propone el diagnóstico de EK en caso de anomalías coronarias (al menos una arteria coronaria dilatada de diámetro interno ? 2,5 SD de la media normalizada para la superficie corporal (puntuación Z), determinado por ecocardiografía). Con fin indicativo, en caso de KD incompleta otros criterios de apoyo biológicos pueden ayudar a confirmar el diagnóstico: leucocitosis, CRP elevada, ESR elevada, anemia, hiponatremia, ASAT, ALAT y gGT elevadas, hiperlipidemia.
4. Paciente que no responde a un tratamiento standard de EK: p. ej., persistencia o recrudescencia de fiebre ? 38°C 48 horas después de la infusión de 2g/kg de IG IV. El intervalo puede reducirse a 24h después del término de la infusión si el paciente sigue febril 24h después del término de la infusión.
5. Es indispensable el consentimiento informado y escrito del paciente, sus padres o responsables legales.
6. Paciente con seguro de salud.
7. Paciente que acepta mantener una contracepción eficaz durante su participación en la investigación. |
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E.4 | Principal exclusion criteria |
1. Preterm and neonates, pregnancy (+?-hCG if appropriate)
2. Patients suspected with another diagnosis
3. Patients with overt concomitant bacterial infection
4. Patients previously treated with steroids or/and another biotherapy
5. Patients with any type of immunodeficiency or cancer
6. Patients with increased risk of Tuberculosis (TB) infection
7. Recent tuberculosis infection or with active TB
8. Close contact with a patient with TB
9. Patients recently arrived less than 3 months from a country with high prevalence of TB
10. A chest radiograph suggestive of TB
11. Patients with end stage renal disease: NKF stages ?4; eGFR?29mL/min/1.73 m2 or diabetes mellitus or neutropenia <1500/mm3 or liver failure
12. Hypersensitivity to the active substance or to any of the excipients (citric acid and anhydrous; sodium chloride disodium edetate dehydrate polysorbate 80; sodium hydroxide; water for injections)
13. Patient already included in a biomedical research other than observational (e.g.; cohort, registry) |
1. Prematuros y neonatos, embarazo (+?-hCG si corresponde)
2. Pacientes en que se sospecha otro diagnóstico
3. Pacientes con infección bacteriana declarada concomitante
4. Pacientes previamente tratados con esteroides y/u otra bioterapia
5. Pacientes con cualquier tipo de inmunodeficiencia o cáncer
6. Pacientes con riesgo mayor de infección tuberculosa (TB)
7. Infección tuberculosa reciente o TB activa
8. Contacto cercano con un paciente con TB
9. Pacientes recién llegados (menos de 3 meses) desde un país con alta prevalencia de TB
10. Radiografía de tórax que sugiere TB
11. Pacientes con enfermedad renal en etapa terminal: etapas NKF ?4; eGFR?29mL/min/1.73 m2 o diabetes mellitus o neutropenia <1500/mm3 o insuficiencia hepática
12. Hipersensibilidad a la sustancia activa o a cualquier excipiente (ácido y anhídrido cítrico; cloruro de sodio; edetato bisódico deshidratado; polisorbato 80; hidróxido de sodio; agua para inyecciones)
13. Paciente ya incluido en un estudio biomédico que no sea sólo observacional (p. ej., cohorte, registro) |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary statistical analysis of the proportion of patients succeeding to reach a body temperature <38°C within 24 hours of treatment by anakinra (even after dose escalation if any) at d15 will be purely descriptive through proportion of patients and its Agresti-Coull confidence interval at 95%. Based on the Intent-To-Treat principle, all included patients will be taken into account. |
El analisis estadistico primirio se centrara en la proprocion de pacientes que alcanzaron une tempertura corporal < 38°C en las 24 horas despues del trazamiento con anakinra en el dia 15. (incluso despues de un aumento de la dosis si es necesario). Este analisis sera puramente descriptivo con un intervalo de confianza Agresti-Coull a 95%, basado en el principio de intencion de tratar a los pacientes, todo paciente incluido sera tomado en cuenta en el analisis |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
at the end of the study |
al final del estudio |
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E.5.2 | Secondary end point(s) |
Secondary analyses: proportion of patients achieving secondary endpoints and their confidence intervals at 95% in all included patients. Safety analyses: descriptive only on all treated patients |
Análisis secundarios: proporción de pacientes que alcanzan los objetivos finales secundarios e intervalos de confianza de 95%, incluyendo a todos los pacientes. Análisis de seguridad: sólo descriptivos, en todos los pacientes tratados |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
at the end of the study |
al final del estudio |
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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 | No |
E.6.5 | Efficacy | No |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
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 | No |
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 | 12 |
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 | 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 | 1 |
E.8.9.2 | In all countries concerned by the trial days | 0 |