| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Children under the age of 2 years having surgery lasting at least 2 hours |
| Bambini sotto i due anni sottoposti ad intervento chirurgico della durata di almeno di 2 ore |
|
| E.1.1.1 | Medical condition in easily understood language |
| Children under the age of 2 years having surgery lasting at least 2 hours |
| Bambini sotto i due anni sottoposti ad intervento chirurgico della durata di almeno di 2 ore |
|
| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10018060 |
| E.1.2 | Term | General anaesthesia |
| E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
|
| 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 |
| Determine if, in children less than 2 years of age having anaesthesia expected to last 2 hours or longer, low-dose sevoflurane/dexmedetomidine/remifentanil anaesthesia is superior to standard dose sevoflurane anaesthesia in terms of the global cognitive function as assessed by the full scale IQ score of the Wechsler Preschool and Primary School Intelligence Scale assessed at 3 years of age. |
| Determinare se in bambini di età inferiore o uguale ai due anni sottoposti ad anestesia generale di durata di almeno 2 ore, la combinazione di sevoflurano a basso dosaggio / dexmedetomidina / remifentanil sia superiore a sevoflurano a dose standard in termini di funzioni neuro-cognitive globali misurate con il punteggio QI della Wechsler Preschool e Primary School Intelligence Scale e valutate a 3 anni di età. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives include determining if, in children less than 2 years of age having anaesthesia expected to last 2 hours or longer, low-dose sevoflurane/dexmedetomidine/remifentanil anaesthesia is superior to standard dose sevoflurane anaesthesia in terms of:
a) a range of other neurodevelopmental tests performed at 3 years of age including subscales of general cognitive functioning, language, executive function, memory, adaptive behaviour, clinical behaviour and social skills.
b) diagnosis of any neurodevelopment disorder at 3 years of age.
c) incidence of intra-operative hypotension,
d) intra-operative bradycardia,
e) post-operative pain,
f) time to recovery,
g) PK/PD determination only in patients treated with dexmedetomidine. |
Determinare se in bambini di età inferiore o uguale ai due anni sottoposti ad anestesia generale di durata di almeno 2 ore, la combinazione di sevoflurano a basso dosaggio / dexmedetomidina / remifentanil sia superiore a sevoflurano a dose standard in termini di:
a) una serie di altri test per lo sviluppo neurologico eseguiti a tre anni d’età, incluso sottoscale delle funzionalità cognitive generali, del linguaggio, delle funzioni esecutive, della memoria, del comportamento adattivo, del comportamento clinico e delle abilità sociali;
b) diagnosi di eventuali disordini dello sviluppo neurologico a tre anni d’età.
c) incidenza di ipotensione intraoperatoria,
d) bradicardia intraoperatoria,
e) dolore post-operatorio,
f) tempo di recupero,
g) determinazione di PK/PD solo nei pazienti sottoposti a trattamento con dexmedetomidina. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Younger than 2 years old (chronological age)
- Scheduled for anaesthesia that is expected to last at least 2 hours (and/or total operating room time is scheduled to be at least 2.5 hours) and for a maximum of 6 hours
- Type of surgery that can be included, assuming patients do not meet exclusion criteria, are the following:
a) Craniofacial (i.e., isolated cleft lip, craniosynostosis, dermoid cysts of the scalp, etc.)
b) Thoracic (i.e., isolated lung malformations, diaphragmatic hernia Morgagni type, etc.)
c) Abdominal (i.e., Hirschsprung disease, Meckel resection, etc.)
d) Urologic (i.e., hypospadias, laparoscopic/robotic hydronephrosis repair, etc.)
e) Orthopaedic (i.e., congenital hip dislocation, bilateral congenital clubfoot, etc.)
f) Neurosurgical (i.e., isolated spine tethering, brachial plexus repair, etc.) |
- Età inferiore ai 2 anni (età cronologica)
- Pianificata anestesia generale di almeno 2 ore (e/o tempo totale in sala operatoria di almeno due ore e mezza) e per un massimo di 6 ore
- Le tipologie di interventi chirurgici che possono essere inclusi, supponendo che i pazienti non soddisfino i criteri di esclusione, sono i seguenti:
a) Craniofacciale (es. labbro leporino isolato, craniosinostosi, cisti dermoide del cuoio capelluto, ecc.)
b) Toracico (es. malformazioni polmonari isolate, ernia diaframmatica di tipo Morgagni, ecc.).
c) Addominale (es. malattia di Hirschsprung, resezione di Meckel, ecc.).
d) Urologico (es. ipospadia, riparazione laparoscopica / robotica dell'idronefrosi, ecc.).
e) Ortopedico (es. lussazione congenita dell'anca, piede torto bilaterale congenito, ecc.).
f) Neurochirurgico (es. legamento isolato della colonna vertebrale, riparazione del plesso brachiale, ecc.). |
|
| E.4 | Principal exclusion criteria |
- Known neurologic, chromosomal or congenital anomaly which is likely to be associated with poor neurobehavioural outcome
- Existing diagnosis of behavioural or neurodevelopmental disability
- Prematurity (defined as < 36 weeks gestational age at birth)
- Birth weight less than 2 kg
- Congenital cardiac disease requiring surgery
- Intracranial neurosurgery and intracranial craniofacial surgery (isolated cleft lip is not an exclusion)
- Previous cumulative exposure to general anaesthesia exceeding 2 hours
- Planned future cumulative exposure to anaesthesia exceeding 2 hours before the age of 3 years.
- Any specific contra-indication to any aspect of the protocol.
- Previous adverse reaction to any anaesthetic
- Circumstances likely to make long-term follow-up impossible
- Living in a household where the primary language spoken at home is not a language in which we can administer the Wechsler Preschool and Primary School Intelligence Scale
- Planned postoperative sedation with any agent except opioids (e.g., benzodiazepines, dexmedetomidine, ketamine, barbiturates, propofol, clonidine, chloral hydrate, and other non-opioid sedatives). For example, if such sedation is planned for post-operative ventilation
- Known hypersensitivity to the study investigational medicinal products (IMPs) and their excipients
- Renal impairment, defined as eGFR < 60 mL/min/1.73 m2, as calculated with Schwartz formula (eGFR = 0.5 × height (cm)/plasma creatinine)
- Hepatic impairment, defined as levels of AST or ALT 3 times above the upper limit of the range of normality, or levels of total bilirubin 2 times above the upper limit of the range
of normality, as reported by the local lab
- Advanced heart block (grade 2 or 3), unless paced
- Uncontrolled hypotension
- Acute cerebrovascular conditions |
- Nota anomalia neurologica, cromosomica o congenita che può essere correlata ad uno scarso esito neurocomportamentale
- Diagnosi esistente di disabilità comportamentali o del neurosviluppo
- Prematurità (definita come età gestazionale alla nascita <36 settimane)
- Peso alla nascita inferiore a 2 Kg
- Cardiopatia congenita che richiede intervento chirurgico
- Interventi neurochirurgici intracranici e interventi intracranici cranio-facciali (il labbro leporino non comporta esclusione)
- Precedente esposizione cumulativa ad anestesia generale superiore a due ore
- Prevista esposizione cumulativa futura ad anestesia generale superiore a due ore prima dei tre anni d’età
- Qualsiasi controindicazione specifica a qualsiasi aspetto del protocollo di studio
- Precedenti reazioni avverse a qualsiasi anestetico
- Circostanze che potrebbero impedire il follow-up a lungo termine
- Famiglia in cui la lingua primaria parlata in casa non è una lingua in cui si possa somministrare la Wechsler Preschool and Primary Scale of Intelligence
- Sedazione postoperatoria programmata con qualsiasi farmaco tranne gli oppioidi (es. benzodiazepine, dexmedetomidina, ketamina, barbiturici, propofol, clonidina, idrato di cloralio e altri sedativi non oppioidi)
- Nota ipersensibilità ai farmaci in studio ed ai loro eccipienti
- Disfunzione renale, definita come filtrato glomerulare stimato (eGFR) < 60 mL/min/1,73 m2, calcolato con la formula di Schwartz (eGFR = 0,5 × altezza (cm) / creatininemia sierica)
- Disfunzione epatica, definita come livelli di AST o di ALT 3 volte al di sopra del limite superiore dell'intervallo di normalità, o livelli di bilirubina totale 2 volte al di sopra del limite superiore dell'intervallo di normalità, come riportato dal laboratorio locale
- Blocco cardiaco avanzato (grado 2 o 3), a meno che non sia stimolato
- Ipotensione non controllata
- Condizioni cerebrovascolari acute |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Full scale IQ score of the Wechsler Preschool and Primary School Intelligence Scale assessed |
| Punteggio QI della Wechsler Preschool and Primary School Intelligence Scale |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 3 years of age of the patient |
| 3 anni di età del paziente |
|
| E.5.2 | Secondary end point(s) |
Safety
- Nature and incidence of adverse events and serious adverse events; Neuropsychological tests
• Language (Clinical Evaluation of Language Fundamentals- Preschool, Version 2)
• Attention/Executive Function/impulse control: (NEPSY-2: Statue Subtest)
• Memory: (NEPSY-2: Narrative memory)
• Adaptive Behaviour: (Adaptive Behavior Assessment System, 3rd Ed 0-5 years)
• Clinical Behaviour: (Child Behavior Checklist for ages 1.5-5 years)
• Executive Function: (Behavior Rating of Executive Function- Preschool)
• Social Skills: Social Skills Improvement System; Anaesthesia
- Incidence of intra-operative hypotension
- Intra-operative bradycardia
- Post-operative pain (FLACC Scale: Face, Legs, Activity, Cry, Consolability Scale)
- Time to recovery |
Sicurezza
- Natura e incidenza di eventi avversi e eventi avversi gravi; Test neuropsicologici
- Linguaggio (Language Fundamentals- Preschool, versione 2)
- Attenzione / funzione esecutiva / controllo degli impulsi (NEPSY-2)
- Memoria (NEPSY-2)
- Comportamento adattivo (Adaptive Behavior Assessment System, 3rd Ed 0-5 anni)
- Comportamento clinico (Child Behavior Checklist, età 1,5 - 5 anni)
- Funzione esecutiva (Behavior Rating of Executive Function- Preschool)
- Competenze sociali (Social Skills Improvement System); Anestesia
- Incidenza di ipotensione intraoperatoria
- Bradicardia intraoperatoria
- Dolore post-operatorio (scala FLACC)
- Tempo di recupero |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
From visit 1 to visit 5; 3 years of age of the patient; - Incidence of intra-operative hypotension - visit 3
- Intra-operative bradycardia - visit 3
- Post-operative pain (FLACC Scale: Face, Legs, Activity, Cry, Consolability Scale) - visits 4 and 5
- Time to recovery - visits 4 and 5 |
Da visita 1 a visita 5; 3 anni di età del paziente; - Incidenza di ipotensione intraoperatoria - visita 3
- Bradicardia intraoperatoria - visita 3
- Dolore post-operatorio (scala FLACC) - visite 4 e 5
- Tempo di recupero - visite 4 e 5 |
|
| 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) | 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 | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Valutatore in cieco |
| assessor blinded |
|
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
| 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 | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| 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 |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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