Title: 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
Funder: Department of Health and Social Care

Abstract: 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

Lay abstract: BACKGROUND The hospital anaesthetic room is a worrying place for a child, and reducing their distress leads to a better overall experience, and also improves recovery from the anaesthetic, reduces pain after surgery and avoids unnecessary reappointments & delays to operations. Currently, those children with high levels of distress are recommended a “premedication”; that is, a medicine to reduce anxiety ahead of surgery. Midazolam – the current premedication for an anxious child needing an anaesthetic – is effective, although it has many side-effects including loss of coordination and risks to breathing. Midazolam can also have unpredictable effects on anxiety, with some children becoming overexcited rather than being calmed. Melatonin, an alternative calming medicine, has shown promise as it avoids midazolam’s side-effects. AIMS We will compare melatonin with midazolam in anxious children undergoing general anaesthetic for dental & ear-nose-throat (ENT) surgeries. These two types of treatment are the most common reasons for children to have an anaesthetic in the UK, and are also easy to compare. We shall carry out the research in 10 large hospitals across England including specialist children’s centres. METHODOLOGY This will be a “randomised” trial in which consenting patients, scheduled for planned dental or ENT surgery, will be allocated to one of 2 groups. Group 1 will receive the usual premedication, midazolam, and Group 2 will receive the premedication to be compared, melatonin. We will look at children’s anxiety from the time of entering hospital until being given the anaesthetic to see if there is a difference between how good the two medicines are at calming children. We will also look at the side-effects of each medicine and assess the cost of each medicine to the NHS. After the operation a research nurse will continue to look for side effects until each child leaves hospital. The nurse will also assess for other beneficial effects thought to occur with using melatonin, such as reducing the confusion and distress that can come after an operation as a child wakes up. Parents/guardians will be phoned 2 weeks after the operation to check no problems have occurred after leaving hospital and also to complete a final questionnaire. The views of those people who the treatment is aimed at are very important to us, and we have designed the study having taken advice from children who have already experienced a general anaesthetic for dental and ENT treatment. They have helped us identify the most important things for the trial to assess and have also provided advice on how the trial should be done. In order to get more information about what the children receiving melatonin or midazolam felt about their treatment, we will invite some of the children to return after the main study to discuss how the trial went. We will ask more in-depth questions about their experience, whether they felt the medicine worked well and how acceptable it was to them. EXPECTED OUTCOMES AND IMPLICATIONS Our work will help determine whether melatonin is a better premedication than midazolam, and we will aim to change NHS policy on premedications in children should melatonin be found to be as good as midazolam at calming anxious children, but with less side effects. We will submit reports of our work to healthcare policy makers and share our findings with both patient and doctor networks so that this change can be brought about.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH