Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621001606875
Ethics application status
Approved
Date submitted
17/06/2021
Date registered
25/11/2021
Date last updated
15/09/2024
Date data sharing statement initially provided
25/11/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
The effect of clonidine on pain post-tonsillectomy in children
Scientific title
A randomised controlled trial investigating the efficacy of Clonidine to help improve the management of pain post-tonsillectomy in children (CHIMP)
Secondary ID [1] 304506 0
NIL
Universal Trial Number (UTN)
Trial acronym
CHIMP
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pain following tonsillectomy surgery 322373 0
Condition category
Condition code
Anaesthesiology 320035 320035 0 0
Pain management
Oral and Gastrointestinal 320036 320036 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
Surgery 320408 320408 0 0
Other surgery

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

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 clonidine (10mcg/ml) suspension or placebo suspension.The blinding of the drug will be performed by the Clinical Trials Pharmacy who will provide us with the unblinding folders/envelopes for the study. Participants, research assistants, nurses and doctors will be blinded to the allocation.

Patients will receive 3mcg/kg (max 150 mcg) of their assigned suspension (rounded to the nearest 0.1 ml) for their first perioperative dose, 30-45 minutes prior to surgery induction. Subsequently, on days 0, 1, 2, 3, 4 and 5 they will receive 1 mcg/kg (0.1 ml/kg, max 50mcg) of their assigned suspension in the morning and at 2pm by mouth, and 2mcg/kg (0.2 ml/kg, max 100 mcg) at night by mouth. Then on days 6 and 7 they will receive 0.5mcg/kg (0.05ml/kg) in the morning and 1mcg/kg (0.1ml/kg) at night. Participants will receive enough doses day 0 (day of surgery) – day 7.

The study medications are in addition to the standard medications normally prescribed post tonsillectomy.In the absence of allergies or adverse drug reactions or contraindication, all patients will be prescribed a weight-based regimen of QID paracetamol (15mg/kg) and TDS ibuprofen (10mg/kg) for 7 days postoperatively. Oxycodone (6-hourly PRN) will be also prescribed to all patients. All patients will be given a ‘test dose’ of oxycodone while in hospital to demonstrate its safety to parents and asses patient tolerance. Children without additional risk factors for opioid-related complications will receive oxycodone at 0.1mg/kg of ideal body weight according to our institutional guidelines. Ten-to fifteen doses of oxycodone (1mg/ml syrup) will be dispensed on discharge (up to maximum of 50mls) if patients maintain their oxygen saturation >92% on room air and without excessive sedation following the test dose. The clinical team on review of test dosing may then decide to use a lower oxycodone dose of 0.05mg/kg or avoid this entirely. Four ondansetron 4mg wafers will also be dispensed for use on the first two mornings and then as required as per usual discharge protocol. The patient receiving clonidine/placebo will have tolerated it for at least 3 doses in hospital prior to discharge without any adverse event attributable to the medication being observed.

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.

After the recruitment of the first 50 patients there will be a review of the postoperative CO2 and Spo2, mean heart rates and mean blood pressure during the first postoperative night.
Intervention code [1] 320867 0
Treatment: Drugs
Comparator / control treatment
Placebo controlled.
Placebo contains Visco-Plus, Denatorium Benzoate, Visco-Sweet
Control group
Placebo

Outcomes
Primary outcome [1] 327899 0
The primary outcome measure will be self-reported pain intensity using the Face Pain Scale – revised (FPS – R)
Timepoint [1] 327899 0
Assessed 4 times daily for 7 days post tonsillectomy.
Parents/ patients will be asked to rate pain intensity twice in the morning and twice in the evening. At each time point the patients will be asked to rate their pain just before the meal (pain at rest) and then again with eating (pain on swallowing).
Secondary outcome [1] 396962 0
A composite secondary outcome of observed daily pain score as measured by the (a) Post-Operative Parental Pain Measure (PPPM) and (b) parent reported pain score (Verbal Rating Scale [VRS] 0 – 10) between the clonidine group and placebo group.
Timepoint [1] 396962 0
Each day post tonsillectomy for a minimum of 14 days or until the child is pain free without analgesia and has returned to normal activities
Secondary outcome [2] 396963 0
"As required’ opioids (no. of doses and total oral Morphine equivalents following surgery and post discharge by each group). These will be assessed through review of medical records and parental recording of all medications administered at home which will be reported via daily survey responses.
Timepoint [2] 396963 0
Each day post tonsillectomy for a minimum of 14 days or until the child is pain free without analgesia and has returned to normal activities
Secondary outcome [3] 396964 0
Composite outcome of unplanned medical re-presentations for (a) pain and (b) any other reason following surgery.
These will be assessed through review of parental responses over the follow-up period. The responses are to the questions in the study specific Diary Booklet that participants receive.
Timepoint [3] 396964 0
Post tonsillectomy for a minimum of 14 days or until the child is pain free without analgesia and has returned to normal activities
Secondary outcome [4] 396965 0
Acceptability of clonidine suspension to parent and patient pre-operatively and postoperatively, as judged by feedback, compliance with dosing and reported side effects, assessed through parental response to follow-up survey questions from the study specific diary booklet that participants receive and review of medical records where necessary.

Based on data from pre-existing literature possible risks of clonidine include:
1. Sedation, dizziness, orthostatic hypotension, dry mouth (1/10)
2. Depression, sleep disorder, headache, constipation, nausea and vomiting (1/100 to < 1/10)
3. Delusion perception, hallucination, nightmare, sinus bradycardia, Raynaud's phenomenon, pruritus, rash, urticaria (1/1000 to 1/100)
4. Anaphylaxis (not known)
Very common side effects which affect more than 1 persons in 10 include sedation, dizziness, orthostatic hypotension, dry mouth.
These will be assessed through review of parental survey responses from the study specific diary booklet that participants receive over the follow-up period and review of medical records if necessary.
Timepoint [4] 396965 0
Post tonsillectomy followup is for a minimum of 14 days or until the child is pain free without analgesia and has returned to normal activities
Secondary outcome [5] 396966 0
Composite outcome: Safety outcome for the first 50 patients: Comparison of the postoperative CO2 and Oxygen Saturation (SpO2), mean heart rates and mean Blood pressure in the first postoperative night between the clonidine and the placebo group.
These will be assessed using:
CO2- transcutaneous CO2 monitoring via forehead probe
Sp02- finger or toe pulse oximeter
Heart rate- measured through the transcutaneous CO2 monitor
Blood pressure is recorded as part of routine clinical care using a blood pressure cuff and monitor
The measurements will be assessed via medical record review or review of data recorded on the monitoring equipment.
Timepoint [5] 396966 0
First postoperative night

Eligibility
Key inclusion criteria
Children aged 4 – 16 years
Undergoing elective surgery under general anaesthesia for tonsillectomy +/- adenoidectomy +/- grommets or cautery of inferior turbinates
Staying overnight in hospital
Minimum age
4 Years
Maximum age
16 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Known cerebrovascular disease, heart failure, occlusive peripheral vascular disorders, such as Raynaud’s disease, cardiac arrhythmias
Known cardiovascular, respiratory or neurological disorders giving an ASA 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)

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)
Allocation concealment by numbered containers of clonidine/placebo syrup
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computer-generated block randomisation will be used.
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
The data will be analysed as a mixed effects repeated measures model. The analysis will indicate any differences in the two treatments (clonidine or placebo) and the change in pain score over time (days). More specifically the model will include the effect of treatment, and measurement conditions (at rest or swallowing), both over time. A random intercept for subject (to account for different baseline pain scores), and a subject-specific random slope will be considered for measurement condition. Fixed effects will include treatment, time trajectory, measurement condition and other study measurements detailed above (such as demographic variables Age, ASA, etc.). A time-treatment interaction term will be included to test the primary hypothesis. The expected trajectory of pain attenuation over time is expected. However, a steeper slope for the trajectory is expected if clonidine significantly reduces the pain score. Non-linear (quadratic or negative exponential) time terms may also be appropriate and will be based on data exploration.

Note that the longitudinal nature of the model will allow missing responses at a few time points. If substantial pain measurement data is missing then a decision will be made 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 cumulative link mixed model, which can test for a difference between treatment means over time (days 1 to 7) [50, 51]. Both models could be fitted for comparison.

The primary hypothesis will be tested based on the difference in slopes of the treatments over time, as obtained from the time-treatment interaction.

Regarding secondary outcomes, these will be assessed as follows. We will also record analgesic medications given on the day of surgery in PACU, on the ward and on each day at home. Any adverse events that occur during the hospital stay will also be recorded. This will allow analysis of analgesic use and compliance with prescribed regime.

Daily Pain intensity scores as reported by parents (PPPM and NRS scales) will be analysed using a similar model as used for the children’s pain scores.

The amount of opioid administered to each group over the days will be analysed as a repeated measures model.

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

Other variables like side effects, UMSS, PAEDS, adverse events, compliance with medication, and need for oxygen therapy following PACU for each group will be analysed using a contingency table using a chi square test of association.

The global satisfaction for treatment by parents will be analysed as a contingency table using a chi square test of association, or as a binomial log-linear model.

Demographics (age, weight, ASA, length of stay and operation data) will be included in the statistical modelling. Summary statistics will also be presented to enable and simplify direct group comparisons.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
15/12/2021
Actual
16/02/2022
Date of last participant enrolment
Anticipated
31/12/2025
Actual
Date of last data collection
Anticipated
15/01/2026
Actual
Sample size
Target
200
Accrual to date
151
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 19762 0
Perth Children's Hospital - Nedlands
Recruitment postcode(s) [1] 34403 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 308872 0
Hospital
Name [1] 308872 0
Perth Children's Hospital
Country [1] 308872 0
Australia
Funding source category [2] 311309 0
Government body
Name [2] 311309 0
Department of Health
Country [2] 311309 0
Australia
Funding source category [3] 317413 0
Government body
Name [3] 317413 0
WA Health RTP
Country [3] 317413 0
Australia
Primary sponsor type
Hospital
Name
Perth Children's Hospital
Address
Child & Adolescent Health Service,
Perth Children's Hospital
15 Hospital Avenue
Nedlands
WA 6009
Country
Australia
Secondary sponsor category [1] 309791 0
None
Name [1] 309791 0
Address [1] 309791 0
Country [1] 309791 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308777 0
Child & Adolescent Health Service HREC
Ethics committee address [1] 308777 0
Ethics committee country [1] 308777 0
Australia
Date submitted for ethics approval [1] 308777 0
17/11/2020
Approval date [1] 308777 0
28/07/2021
Ethics approval number [1] 308777 0
RGS0000003995

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 111846 0
Prof Britta Regli-von Ungern-Sternberg
Address 111846 0
Perth Children's Hospital
15 Hospital Avenue
Nedlands
WA 6009
Country 111846 0
Australia
Phone 111846 0
+61 420790101
Fax 111846 0
Email 111846 0
[email protected]
Contact person for public queries
Name 111847 0
Britta Regli-von Ungern-Sternberg
Address 111847 0
Perth Children's Hospital
15 Hospital Avenue
Nedlands
WA 6009
Country 111847 0
Australia
Phone 111847 0
+61 420790101
Fax 111847 0
Email 111847 0
[email protected]
Contact person for scientific queries
Name 111848 0
Britta Regli-von Ungern-Sternberg
Address 111848 0
Perth Children's Hospital
15 Hospital Avenue
Nedlands
WA 6009
Country 111848 0
Australia
Phone 111848 0
+61 420790101
Fax 111848 0
Email 111848 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.