| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| sedation in intensive care |
| sedación en cuidados intensivos |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Anesthesia and Analgesia [E03] |
| 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 | 10039897 |
| E.1.2 | Term | Sedation |
| E.1.2 | System Organ Class | 10029205 - Nervous 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 assess the non-inferiority of the sedative properties of continuous intravenous (i.v.) clonidine compared to continuous i.v. midazolam in mechanically ventilated children and adolescents (0 - <18 years) admitted to a paediatric intensive care unit (PICU). |
| Evaluar la no inferioridad de las propiedades sedantes de clonidina intravenosa continua (IV) comparada con midazolam IV continuo en niños y adolescentes (0 - <18 años) con ventilación mecánica ingresados en una unidad de cuidados intensivos pediátricos (UCIP |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the safety and tolerability (including withdrawal effects) of clonidine compared with midazolam in ventilated children and adolescents admitted to PICU.
- To determine clonidine dose-dependent effects on sedation.
- To establish the pharmacokinetics - pharmacodynamics (PK-PD) relationship of clonidine for sedation in PICU.
- To compare the cumulative total morphine consumption/kg between the two arms in the first 48 hours of investigational medical product (IMP) administration.
- To determine if candidate genes predict adequate response to clonidine and midazolam in critically ill paediatric patients.
- To identify polymorphisms of clinical relevance to the sedative action of clonidine, midazolam and morphine.
- To correlate midazolam pharmacokinetics to polymorphisms of candidate genes.
- To correlate clonidine pharmacokinetics to polymorphisms of candidate genes.
-To correlate morphine pharmacokinetics to polymorphisms of candidate genes. |
- Evaluar la seguridad y tolerancia (incluidos los efectos de abstinencia) de la clonidina en comparación con el midazolam en niños y adolescentes con ventilación mecánica ingresados en una UCIP.
- Determinar los efectos dosis dependientes de la clonidina sobre la sedación.
- Establecer la relación PK-PD de la clonidina para la sedación en UCIP.
- Comparar el consumo acumulativo total de morfina / kg entre los dos brazos en las primeras 48 horas de administración del IMP.
- Determinar si los genes candidatos predicen una respuesta adecuada a la clonidina y al midazolam en pacientes pediátricos críticamente enfermos.
- Identificar los polimorfismos con relevancia clínica sobre la acción sedante de la clonidina, el midazolam y la morfina.
- Correlacionar la farmacocinética
del midazolam con polimorfismos de genes candidatos,
de la clonidina con polimorfismos de genes candidatos,
de la morfina con polimorfismos de genes candidatos |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Male or Female
- Aged from birth (≥34 weeks gestational age [GA]) to <17 years, 11 months, 1 week old
- Admitted or expected to be admitted (post-operatively) to PICU
- Existing or expected indication for invasive or non-invasive ventilation (except Continuous Positive Airway Pressure, CPAP)
- Anticipated need for continuous sedation for at least 24 hours
- Informed consent (or deferred consent) obtained from the subject’s parent(s) or legal guardian(s).
- Where applicable, assent obtained from the subject to participate in the clinical trial |
- sujetos masculinos o femeninos
- Edades comprendidas entre el nacimiento (edad gestacional [GA] ≥34 semanas) y <17 años, 11 meses, 1 semana
- Ingresados o con previsión de ser ingresados (post-quirúrgicos) en cuidados intensivos pediátricos
- con indicación establecida o probable de ventilación invasiva o no invasiva (exceptuando la presión positiva continua de las vías respiratorias, CPAP)
- necesidad anticipada de sedación continua al menos 24 horas
- Consentimiento informado (o consentimiento diferido) obtenido de los padres del sujeto o de su tutor legal
- Si procede, asentimiento obtenido del sujeto de estudio para participar en el ensayo clínico. |
|
| E.4 | Principal exclusion criteria |
- Body weight less than 1200 g
- Gestational age [GA] of <34 weeks
- Body weight 3 kg or less AND aged 28 days or older
- Body weight less than 10 kg AND aged 2 years old or older
- Body weight greater than 85 kg.
- Subjects who will be 18 years old in less than 3 weeks
- Known hypersensitivity to the IMP (Clonidine) or comparator (Midazolam), or NIMP (Morphine, Propofol) or any of their formulation ingredients and their rescue medication
- Subjects being treated with forbidden concomitant medications
- Subjects less than 24 hours post-resuscitation
- Subjects who have been under sedation for more than 72 hours immediately prior to assessment
- Subjects currently being treated with Extra Corporeal Membrane Oxygenation (ECMO)
- Subjects with treatment-induced whole body hypothermia
- Subjects with severe organ insufficiencies
- Subjects with traumatic brain injury all grades (due to potential effects on the level of consciousness).
- Subjects with intracranial pathology (tumour, haemorrhage, infections) with an effect on level of consciousness.
- Subjects with severe mental retardation with or without a well-defined syndrome that preclude performance of a COMFORT-B Score.
- Subjects with Myasthenia gravis, Spinal muscular atrophy, or other rare neurologic diseases and conditions which preclude performance of a COMFORT-B Score.
- Subjects with major congenital anomalies of the central nervous system
- Subjects with phaeochromocytoma.
- Subjects with severe bradyarrhythmia resulting from either sick-sinus syndrome or AV block of 2nd or 3rd degree.
- Subjects with current status epilepticus or active fitting (2 or more seizures regularly on a daily basis) at admission.
- Known arterial hypertension requiring chronic treatment in medical history.
- Females who are pregnant, lactating or planning to become pregnant or who return a positive result to a pregnancy test (a dipstick and serum pregnancy test will be performed at the screening visit).
- Employee or direct relative of an employee or any member of the study site staff or the Sponsor/ study management staff (applies to subject and/ or subject’s parent(s).
- Participation in a clinical intervention study using drugs within the last 3 weeks
- Previous participation in this clinical study at any time. |
- Peso corporal inferior a 1200 g.
- Edad gestacional < 34 semanas.
- Peso inferior o igual a 3 kg Y edad superior o igual a 28 días.
- Peso inferior a 10 kg Y edad superior o igual a 2 años.
- Peso mayor de 85 kg.
- Sujetos que cumplirán 18 años en menos de 3 semanas.
- Hipersensibilidad conocida al IMP (Clonidina) o al comparador (Midazolam), o a los NIMP (Morfina y Propofol) o a cualquiera de sus ingredientes o medicaciones de rescate.
- Sujetos tratados con medicaciones concomitantes no permitidas.
- Menos de 24h post-resucitación.
- Sujetos sedados más de 72 h inmediatamente antes de la valoración inicial.
- Sujetos siendo tratados con ECMO.
- Sujetos en tratamiento con hipotermia inducida
- Sujetos con insuficiencias orgánicas severas.
- Sujetos con cualquier grado de trauma craneal. grave (debido al potencial efecto sobre el nivel de conciencia).
- Sujetos con patología intracraneal (tumor, hemorragia, infección) que pueda afectar el nivel de conciencia.
- Sujetos con discapacidad intelectual grave con o sin un síndrome bien definido que impida la realización de la evaluación con la escala COMFORT-B.
- Sujetos con miastenia grave, atrofia muscular espinal, u otra enfermedad o alteración neurológica grave que impida la realización de la evaluación con la escala COMFORT-B.
- Sujetos con anomalías congénitas mayores del sistema nervioso central.
- Sujetos con feocromocitoma.
- Sujetos con bradiarritmias por síndromes sinusales o bloqueos AV de grado 2 o 3.
- Sujetos que presentan status epilepticus o crisis activas ( 2 o más al día de forma regular) al ingreso.
- Hipertensión arterial conocida que por anamnesis requiera tratamiento crónico.
- Mujeres embarazadas, lactando, que prevean quedarse embarazadas, o con resultado positivo en un test de embarazo (la visita inicial incluye pruebas de embarazo serológica y con tira reactiva).
- Empleado o familiar directo de un empleado o de cualquier personal del centro de estudio o del promotor/personal de gestión del estudio (aplica a sujetos y padres de los sujetos).
- Participación en un estudio clínico intervencional con fármacos en las últimas 3 semanas.
- Participación previa en este mismo estudio clínico con cualquier anterioridad. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| proportion of subjects receiving clonidine with sedation failure compared to those subjects receiving midazolam |
| proporción de sujetos que reciben clonidina con fracaso de la sedación comparado a la proporción de sujetos que reciben midazolam |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Sedation and pain assessed at: baseline/ randomization, treatment period, completion visit, post dose monitoring for up to 24 hours. |
| Sedación y dolor valorado: al inicio/randomización, durante el tratamiento, en la visita final, monitorización post-dosis hasta 24h después. |
|
| E.5.2 | Secondary end point(s) |
• Primary PK parameters: clearance (CL), volume of distribution (VD) and inter-compartmental clearance (Q), Cmax, AUC, t1/2, Csteady state, Ctrough.
• PKPD modeling.
• PKPD covariate model
• Safety and tolerability assessments
• Extent of withdrawal effects.
• The extent of delirium.
• Rebound hypertension.
• Percentage of respiratory depression per group.
• Adverse event reporting of symptoms indicative of post-ICU stress.
• Neurodevelopment.
• CYP3A4, CYP3A5, CYP2D6, COMT, OPRM1, OCT1 and UGT2B7 polymorphisms (additional polymorphisms are listed in protocol). |
• Parámetros PK primarios: aclaramiento (CL), volumen de distribución (VD) y aclaramiento inter-compartimental (Q), Cmax, Cestado estacionario, Cvalle
• Modelización PKPD
• Modelización covariables PKPD
• Valoraciones de seguridad y tolerancia
• Intensidad de los efectos de la abstinencia.
• Intenisdad del delirio
• Hipertensión de rebote
• Porcentaje de depresión respiratoria por grupo.
• Informes de reacciones adversas y síntomas indicativos de estrés pos-UCI.
• Neurodesarrollo
• Polimorfismos • CYP3A4, CYP3A5, CYP2D6, COMT, OPRM1, OCT1 y UGT2B7 (en el protocolo se listan además otros polimorfismos). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• PK parameters: treatment period, completion visit, post dose monitoring.
• Safety and tolerability assessments: treatment period, completion visit, post dose monitoring, follow up (14 days post final dose and 1 year post final dose [neonates only]).
• Extent of withdrawal effects, including the extent of delirium: treatment period, completion visit, post dose monitoring for at least 24 hours.
• Rebound hypertension: for at least 72 hours post cessation of treatment.
• Respiratory depression: during re-intubation apnaea in treatment period, completion visit, post dose monitoring every 24 hours.
• Neurodevelopment: at 12 months after cessation of IMP (neonates only).
• Polymorphisms: On 1 day of treatment period only. |
• Parámetros PK: periodo de tratamiento, visita final, monitorización post-dosis.
• Valoraciones de seguridad y tolerancia: periodo de tratamiento, visita final, monitorización post-dosis, seguimiento (14 días después de la dosis final y al año post-dosis [solo para neonatos]).
• Intensidad de los efectos de la abstinencia, incluida la intensidad del delirio: periodo de tratamiento, visita final, monitorización post-dosis hasta 24h después.
• Hipertensión de rebote: al menos 72 h después de fin de tratamiento.
• Depresión respiratoria: durante apnea por reintubación en el periodo de tratamiento, visita final, monitorización post-dosis hasta 24h después.
• Neurodesarrollo: 12 meses después de final de IMP (solo en neonatos).
• Polimorfismos: solo en día 1 del periodo de tratamiento. |
|
| 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 | No |
| 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 | 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
| 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 | 5 |
| 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 | |
| E.8.9.1 | In the Member State concerned months | 14 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 36 |
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