Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12624000252516
Ethics application status
Approved
Date submitted
8/02/2024
Date registered
14/03/2024
Date last updated
14/03/2024
Date data sharing statement initially provided
14/03/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
Does melatonin after tonsillectomy enhance sleep and recovery in children (MATES)?
Scientific title
A multicentre, double blinded randomised controlled trial investigating the efficacy of postoperative Melatonin in improving children’s sleep quality and recovery post-tonsillectomy.
Secondary ID [1] 311154 0
NIL
Universal Trial Number (UTN)
Trial acronym
MATES
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pain following tonsillectomy surgery 332317 0
Condition category
Condition code
Anaesthesiology 329028 329028 0 0
Pain management
Oral and Gastrointestinal 329029 329029 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study will be a randomized, double-blinded and placebo-controlled trial.

Following approval from the treating anaesthetist and voluntary written informed consent by the parent/guardian, the recruited children will be block randomised and assigned to one of the two groups in a 1:1 ratio to receive either a melatonin solution or placebo solution.
As part of the study development, the melatonin dosing was discussed with paediatric pain specialists, respiratory specialists and anaesthetists from Perth Children’s Hospital and other Australian centres. A conservative consensus dosing regime was agreed upon.

Patients will receive their first dose 30-45 minutes prior to their usual bedtime on the day of surgery and continue on days 1-6 post-operatively (total of 7 doses). Children will receive a dose of 0.1 mg/kg (of ideal body weight) to a maximum of 5 mg of melatonin or placebo suspension at night by mouth for all their post operative doses.

As a medical sleeping aid 1-10 mg is considered to be standard.

Sedative premedications administered prior to surgery time (midazolam, clonidine, dexmedetomidine and ketamine) will be allowed as deemed appropriate by the treating anaesthetist.

There will be active follow up with the families to ensure study adherence. All families are provided with a standard diary to document medication administration following tonsillectomy surgery. Our families will also be provided with a study diary where they will document further information. They will also report this in the study database via survey links sent daily.
Intervention code [1] 327594 0
Treatment: Drugs
Comparator / control treatment
Placebo controlled.
The Placebo will look and taste the same as the active melatonin solution. The ingredients will be:
Glycerol USP/BP, Purified water BP, Sucralose NF, Marshmallow flavour and Methyl hydroxybenzoate USP.

Both the melatonin syrup and placebo will be sourced and prepared by OPTIMA OVEST via the Perth Children’s Hospital clinical trials pharmacy.
Control group
Placebo

Outcomes
Primary outcome [1] 336836 0
Assessment of change in the sleep quality of children undergoing tonsillectomy between the pre-operative assessment (baseline) and the assessments at day 7 and day 14 post-operatively.
Timepoint [1] 336836 0
Parents of participants will be asked to answer the PROMIS-8a preoperatively (baseline) and at days 7 (primary endpoint) and 14 post-operatively to assess their child’s sleep quality.
Primary outcome [2] 336837 0
Assessment of post-operative sleep quality of children undergoing tonsillectomy.
Timepoint [2] 336837 0
Parents of participants will be asked to assess their child’s sleep on the 0-10 scale on days 1 to 7 (primary endpoint) and day 10 and 14 post-operatively.
Secondary outcome [1] 429789 0
Assessment of the difference in post-operative sleep quality between the active and control groups.
Timepoint [1] 429789 0
Parents of participants in both the active and control groups will be asked to assess their child’s sleep on the 0-10 scale on days 1-7, 10 and 14 post-operatively.
Secondary outcome [2] 429790 0
Comparison of recorded pain scores between children in the active and control groups.
Timepoint [2] 429790 0
Parents of participants will be asked to assess their child’s pain on days 1-7, and on days 10 and 14 post-operatively.
Secondary outcome [3] 429791 0
Comparison of “as required” opioids between the active and control groups.
Timepoint [3] 429791 0
All “as required” opioid doses given between surgery and 14 days post-operatively will be recorded.
Secondary outcome [4] 429792 0
Comparison of unplanned medical representations for pain or any other reason following surgery between the active and control group.
Timepoint [4] 429792 0
Representation data will be collected during the routine post-tonsillectomy follow up period of a minimum of 14 days or until the child is pain free without analgesia and has returned to normal activities.
Secondary outcome [5] 429793 0
Assessment of the acceptability of melatonin suspension to parents and patients post-operatively.
Timepoint [5] 429793 0
Data on acceptability of melatonin will be collected over the routine post-tonsillectomy follow up period of a minimum of 14 days or until the child is pain free without analgesia and has returned to normal activities.
Secondary outcome [6] 432079 0
Comparison of recorded pain scores between children in the active and control groups.
Timepoint [6] 432079 0
Parents of participants will be asked to assess their child’s pain on days 10 and 14 post-operatively.
Secondary outcome [7] 432085 0
Comparison of recorded pain scores between children in the active and control groups.
Timepoint [7] 432085 0
Participants will be asked to report their pain on days 10 and 14 post-operatively.

Eligibility
Key inclusion criteria
Children aged 2-16 years
Undergoing elective surgery under general anaesthetic for tonsillectomy +/- adenoidectomy +/- grommets or cautery inferior turbinates
Staying overnight in hospital
Minimum age
2 Years
Maximum age
16 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Currently taking Melatonin
• Known cardiovascular, respiratory or neurological disorders giving an American Society of Anaesthesiologists (ASA) physical status classification III or above status
• Known hypersensitivity to the active substance or to any of the excipients listed
• Language barriers impeding data collection
• Department for Child Protection and Family Support is involved in their care
• Planned admissions to the Paediatric Intensive Care Unit (PICU)
• Any concern in the ability of the parents/guardian or child to appropriately adhere to the study protocol or any issues which, in the investigator’s opinion, would increase the risks of study participation to the child.
• Day surgery tonsillectomy

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Sealed opaque envelopes.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computer-generated block randomisation.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Data will be explored using graphical and numeric summaries.
To assess the primary outcome of the change in PROMIS Sleep Disturbance score from pre-operative assessment to 7-days post-op, a model for PROMIS score at day-7 will be fit, with PROMIS score at baseline entered as a moderator, treatment group (melatonin or placebo) and day of measurement (baseline or day-7) as predictors. Covariates will include patient demographic variables and surgical details. Random intercepts for patients within sites will be considered. Similarly, a model for the sleep scores on day 14 will be fitted using the baseline score and the score on day 7 as moderators.

If substantial sleep quality measurement data is missing then a decision will be made (based on the proportion of missing data) either to omit the record from analysis, or to impute the data using a standard technique (such as multiple imputation based on chained equations).

An alternative model is a linear mixed effects repeated measure model including random intercept for subject within-sites and a random intercept for site, and appropriate models for heterogeneous variance, which can test for a difference between treatment means over time (days 1 to 7). A correlation structure for measurements at the three time points will also be included. Appropriate interaction terms will be investigated. The results of all the models will be compared.

Secondary outcomes will be assessed using appropriate statistical modelling methods. The outcome of pain score over time will be analysed as linear mixed-effects repeated measures models, with treatment group, day of measurement, and covariates including patient demographics, medication use, and surgical details. Random intercepts for subjects within sites and site will be used to account for different baseline pain.

Appropriate interaction terms will be investigated. The different pain measures (PPPM-SF, average patient-reported VRS) will be analysed as separate outcomes.
.
The amount of opioid administered to each group over the days will be analysed as a repeated measures model. Alternatively, the total number of breakthrough opioid doses will be analysed using appropriate count regression models (such as Poisson, negative binomial, or zero-inflated).

For each group the number of unplanned medical presentations will be analysed as a Poisson log-linear model or a contingency table using a chi square test of association.

An interim analysis will be performed after 100 recruited patients, 50 in each group, maintaining the blinding, with regard to compliance, side effects and representations. The blinded data will reviewed by the independent Drug Safety Monitoring Committee (DSMC). It can be un-blinded at their request.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
25/03/2024
Actual
Date of last participant enrolment
Anticipated
1/02/2027
Actual
Date of last data collection
Anticipated
15/02/2027
Actual
Sample size
Target
240
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 25940 0
Perth Children's Hospital - Nedlands
Recruitment hospital [2] 26161 0
Fiona Stanley Hospital - Murdoch
Recruitment postcode(s) [1] 41774 0
6009 - Nedlands
Recruitment postcode(s) [2] 42024 0
6150 - Murdoch

Funding & Sponsors
Funding source category [1] 315407 0
Hospital
Name [1] 315407 0
Perth Children's Hospital
Country [1] 315407 0
Australia
Primary sponsor type
Hospital
Name
Perth Children's Hospital
Address
15 Hospital Avenue Nedlands WA 6009
Country
Australia
Secondary sponsor category [1] 317470 0
None
Name [1] 317470 0
Address [1] 317470 0
Country [1] 317470 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 314323 0
Child and Adolescent Health Service Human Research Ethics Committee
Ethics committee address [1] 314323 0
Level 5 Perth Children's Hospital 15 Hospital Avenue Nedlands WA 6009
Ethics committee country [1] 314323 0
Australia
Date submitted for ethics approval [1] 314323 0
27/11/2023
Approval date [1] 314323 0
07/02/2024
Ethics approval number [1] 314323 0
RGS0000006395

Summary
Brief summary
Tonsillectomy is one of the most common childhood surgical procedures, however the postoperative recovery is often long and challenging for children and their families. This study aims to investigate if seven days of oral melatonin is able to improve sleep and pain management in children post-tonsillectomy, without increasing the risk of postoperative complications compared to placebo.

We hypothesise that: (1) Melatonin will improve sleep following tonsillectomy; (2) melatonin will decrease post-operative pain and reduce breakthrough opioid requirement; and (3) melatonin will not increase the risk of post-operative complications.
Trial website
Trial related presentations / publications
None
Public notes

Contacts
Principal investigator
Name 131186 0
Prof Britta Regli-von Ungern-Sternberg
Address 131186 0
Perth Children's Hospital 15 Hospital Avenue Nedlands WA 6009
Country 131186 0
Australia
Phone 131186 0
+61420790101
Fax 131186 0
Email 131186 0
[email protected]
Contact person for public queries
Name 131187 0
Prof Britta Regli-von Ungern-Sternberg
Address 131187 0
Perth Children's Hospital Department of Anaesthesia and Pain Medicine 15 Hospital Avenue Nedlands WA 6009
Country 131187 0
Australia
Phone 131187 0
+61 420790101
Fax 131187 0
Email 131187 0
[email protected]
Contact person for scientific queries
Name 131188 0
Prof Britta Regli-von Ungern-Sternberg
Address 131188 0
Perth Children's Hospital 15 Hospital Avenue Nedlands WA 6009
Country 131188 0
Australia
Phone 131188 0
+61 420790101
Fax 131188 0
Email 131188 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Investigators for the study are still deciding upon how to proceed with this and are awaiting feedback from their HREC


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.