The MAGIC trial (Melatonin for Anxiety prior to General anaesthesia In Children): A Multicentre, Parallel Randomised Controlled Trial of Melatonin Versus Midazolam in the Premedication of Anxious Children Attending for Elective Dental and ENT Surgery Under General Anaesthesia

DESIGN: Multicentre, parallel group, non-inferiority, pragmatic, observer blinded, RCT SETTING: Secondary care; elective dental/ENT surgical cases at 10 centres TARGET POPULATION: Children (6-14yrs) undergoing elective dental/ENT surgery under General Anaesthesia (GA) with high pre-operative distress INCLUSION: Assessed by healthcare professional as requiring premedication for high/expected high levels of preoperative distress prior to elective dental/ENT surgery under GA; ASA grades I & II; not currently prescribed melatonin/midazolam; aged 6-14 EXCLUSION: Severe learning disability - child unable to communicate even with specialised support HEALTH TECHNOLOGY ASSESSED: Control: midazolam 0.5mg/kg Intervention: Immediate release melatonin 0.5mg/kg Both oral 30 mins prior to theatre transfer, 20mg capped dose MEASUREMENT OF COSTS & OUTCOMES: Primary outcome: Preoperative distress by modified Yale Preoperative Anxiety Scale (m-YPAS) Clinical: Emergence agitation (PAED index), postoperative sedation (Vancouver Sedation Recovery Scale, recovery time), postoperative pain (Revised Faces Pain Scale, FPS-R; postoperative analgesia requirements, local anaesthetic amount), failed anaesthesia, psychomotor, orientation Patient-reported: Post-discharge behaviour, eating, anxiety, aggression, apathy & sleep disturbance post-surgery (Post-Hospital Behaviour Questionnaire; PHBQ), parental Stait Trait Anxiety Index Qualitative: Patient, parent & stakeholder acceptability of trial procedures and drug (interview schedule), Economic: Cost-effectiveness analysis (health-related quality of life; CHU9D, clinical time utilisation; anaesthetic time, recovery time, patient turnaround time) Adverse events include: respiratory depression postoperative vital signs, nausea & vomiting SAMPLE SIZE: 592 (296 per arm) is sufficient to declare non inferiority under the assumptions: 1 baseline and three timepoints evaluated (correlation 0.5), 90% power, 1 sided alpha of 2.5%, no difference between drugs, non inferiority margin of 4.3 points, SD of 25 points. The standardised non inferiority margin (0.17) is a third of the standardised placebo contrasted Minimum clinically Important difference (MCID) (0.48) from Jenkins et al (Anesth Analg. 2014;119:643). Accounting for 5% drop out, 624 subjects will be randomised DIFFERENCE BETWEEN CURRENT & PLANNED CARE PATHWAYS: Exchange midazolam (Schedule 3 controlled drug) for melatonin (not controlled drug); care pathway otherwise unchanged ANALYSIS: To be reported according to the CONSORT statement. Primary outcome (as well as continuous secondary outcome) to be analysed by a mixed model fitting the terms treatment, time, baseline as covariate. A logistic regression will be used to evaluate categorical outcomes. Sensitivity analyses will be used to evaluate robustness PROJECT TIMETABLES INCLUDING RECRUITMENT RATE: Recruit n=5/month (average) at 10 centres. 36m study: 10m set-up; 18m recruitment; 1m follow-up; 1m closeout and 6m analysis & write-up. Internal pilot evaluates objective stop-go criteria based on m11-17, using traffic-light system; green light criteria of (1)n=156 (80%) participants randomised;(2)expected protocol;(3)80% retention EXPERTISE IN TEAM: Multidisciplinary team including different clinical specialities (paediatric dental, oral surgery, ENT, anaesthetics) across 10 UK centres, methodologists (trial management, statistics & health economics), NIHR trials experience and FiCTION trial Chief Investigator to support successful implementation