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Trial registered on ANZCTR


Registration number
ACTRN12615000456550
Ethics application status
Approved
Date submitted
20/03/2015
Date registered
11/05/2015
Date last updated
20/12/2018
Date data sharing statement initially provided
20/12/2018
Date results information initially provided
20/12/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Maxigesic Oral Suspension for Children undergoing Tonsillectomy
Scientific title
A randomized, single-blind, parallel group, comparison of the pharmacokinetic profiles, dose response, analgesic effectiveness and safety of high and low dose of a paracetamol and ibuprofen fixed dose combination in children undergoing tonsillectomy with or without adenoidectomy
Secondary ID [1] 286384 0
AFT-MX-12
Universal Trial Number (UTN)
U1111-1167-9926
Trial acronym
Maxigesic Oral Suspension Tonsillectomy Study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Post Tonsillectomy Pain Relief 294527 0
Condition category
Condition code
Anaesthesiology 294834 294834 0 0
Pain management
Surgery 294938 294938 0 0
Other surgery

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Maxigesic oral suspension: paracetamol 160mg + ibuprofen 48mg / 5 mL
a) Corresponding doses: low dose: paracetamol 12mg/kg + ibuprofen 3.6 mg/kg;
b) The frequency and duration of administration: 4-6 hourly for 2 days post surgery
c) the mode of administration, oral suspension
d) Strategies used to monitor the compliance: IPs will be returned and documented in the accountability Log
Intervention code [1] 291451 0
Treatment: Drugs
Comparator / control treatment
Maxigesic oral suspension: paracetamol 160mg + ibuprofen 48mg / 5 mL
a) Corresponding doses:high dose:paracetamol 15mg/kg + ibuprofen 4.5 mg/kg
b) The frequency and duration of administration: 4-6 hourly for 2 days post surgery
c) the mode of administration, oral suspension
d) Strategies used to monitor the compliance: IPs will be returned and documented in the accountability Log
Control group
Active

Outcomes
Primary outcome [1] 294598 0
Study Period 1: To characterize the pharmacokinetic profile of two different dose regimes of a fixed dose paracetamol and ibuprofen combination (Maxigesic oral suspension) in children between 2-12 years of age inclusive by performing the plasma assay (blood samples will be taken during the first 6hrs after the loading dose).
Timepoint [1] 294598 0
Study Period 1: The pharmacokinetic Profile of two different doses of Maxigesic oral suspension including Cmax, Tmax, t1/2, AUC, CL, V, absorption half -time (Tabs), lg time (Tlag) during the first 6 hours after the first dose of study medication. Blood samples for plasma assay will be taken at the following time points:
1. Approximately 30 mins after the loading dose
2. Immediately before leaving the operating room
3. 1 hour after the loading dose
4. 2 hour after the loading dose
5. 3-4 hours after the loading dose
6. 5-6 hours after the loading dose

Primary outcome [2] 294694 0
Study Period 2: To measure pain scores on swallowing using the PPPM's rating on the first post-operative day and to compare the time adjusted Area under the Curves (AUCt)for the two doses of Maxigesic oral suspension after the first dose on postoperative day one until the midnight dose.
Timepoint [2] 294694 0
Study Period 2: Parent's Postoperative Pain Measurement (PPPM) and Wong-Baker Faces Pain Rating assessed on swallowing will be assessed every 2 hrs after the first dose on postoperative day one until the midnight dose.
Secondary outcome [1] 313694 0
Study Period 1: To assess the PK equivalence of individual components administered in the Maxigesic oral suspension combination to single agent therapy PK data in children from the literature. PK profile analysis of the individual components in Maxigesic oral suspension will be performed through the plasma assay. Blood samples will be taken at the time points listed below:
1. Approximately 30 mins after the loading dose
2. Immediately before leaving the operating room
3. 1 hour after the loading dose
4. 2 hour after the loading dose
5. 3-4 hours after the loading dose
6. 5-6 hours after the loading dose

Timepoint [1] 313694 0
Study Period 1: Population Parameter estimates of pharmacokinetic parameters (Volume of Distribution, Absorption Rate Half-time and clearance) obtained using non-linear mixed effects modelling during the first 6 hours after the first dose will be compared with published PK parameters by performing the plasma assay. Blood samples will be taken at the time-points listed below:
1. Approximately 30 mins after the loading dose
2. Immediately before leaving the operating room
3. 1 hour after the loading dose
4. 2 hour after the loading dose
5. 3-4 hours after the loading dose
6. 5-6 hours after the loading dose

Secondary outcome [2] 313874 0
Study Period 2: To measure pain scores prior to swallowing using the PPPM's rating on the first post-operative day and to compare the time adjusted Area under the Curves (AUCt)for the two doses of Maxigesic oral suspension after the first dose on postoperative day one until the midnight dose.
Timepoint [2] 313874 0
Study Period 2: Parent's Postoperative Pain Measurement (PPPM) and Wong-Baker Faces Pain Rating assessed prior to swallowing will be assessed every 2 hrs after the first dose on postoperative day one until the midnight dose.
Secondary outcome [3] 314150 0
Study Period 2: To measure and compare pain scores on the first post-operative day by comparison of time-adjusted AUCt of Wong-Baker Faces Scales after the first dose on postoperative day one until the night time dose prior to and on swallowing for two doses of Maxigesic oral suspension in the subgroup of older children aged 7-12 years of age
Timepoint [3] 314150 0
Study Period 2:Wong-Baker Faces Pain Rating assessed prior to swallowing and on swallowing will be assessed every 2 hrs after the first dose on postoperative day one until the midnight dose in the subgroup of older children aged 7-12 years of age.
Secondary outcome [4] 314151 0
Study Period 2: To compare the amount of rescue medication administered from the first dose on postoperative day one for up to the night-time dose between the two study groups -the consumption of rescue medication will be documented on the participant diary in a self-management style
Timepoint [4] 314151 0
Study Period 2: The amount of rescue medication administered from the first dose on postoperative day one for up to the night dose
Secondary outcome [5] 314152 0
Study Period 2: To compare the time to the first request for rescue medication after the first dose of study medication on post-operative day one between the two study groups
Timepoint [5] 314152 0
Study Period 2: The time to the first request for rescue medication after the first dose of study medication on post-operative day one between the two study groups
Secondary outcome [6] 314153 0
Study Period 2: To compare the percentage of participants requiring rescue medication on postoperative day one between the two study groups
Timepoint [6] 314153 0
Study Period 2: The percentage of participants requiring rescue medication on postoperative day one between the two study groups.

Eligibility
Key inclusion criteria
Children aged 2-12 yrs of age
Scheduled to undergo tonsillectomy with or without adenoidectomy
Written informed consent from parents/legal guardians and assent from participant (where appropriate).
Minimum age
2 Years
Maximum age
12 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Participants declines assent (or consent) or parent declines consent
Two small (weight<10kg at baseline)
Having taken any NSAID or paracetamol within 12hrs prior to the surgery

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)
During the screening, participant's eligibility will be checked.

Randomization will be stratified by age group (2-6 and 7-12 yrs) and the type of surgery (tonsillectomy with or without adenoidectomy). Eligible participant will be randomly allocated to receive either a low dose or high dose of Maxigesic oral suspension.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomization sequence will be generated by computer, by an independent statistician. The statistician will maintain a confidential schedule of patient numbers and drug allocation.

The randomization will be balanced by using permuted blocks and stratifying by age group and the type of surgery. Each eligible participant will be assigned a unique identification number in sequential order. Participants discontinued after the randomization will not be replaced and the next available number shall be used to randomize a new participant.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Phase 2 / Phase 3
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
The PK profile will be derived from the plasma concentration vs time data using non-compartmental methods.

The mean time-adjusted AUC will be compared between two dose groups using ANOVA which includes randomization strata and randomized treatment as fixed effects Standard descriptive statistics including means, medians, ranges and 95% confidence intverals will be used to describe the values .

Study power calculation from the results of a similar study in a pediatric population ( Merry et al. 2013) indicate that 100 participants per group would be required to detect as significant (2-sided alpha=0.05) a 10% difference in mean AUCt between treatment groups with 80% power.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 6690 0
Sunshine Hospital - St Albans
Recruitment postcode(s) [1] 14323 0
3021 - St Albans
Recruitment outside Australia
Country [1] 6764 0
New Zealand
State/province [1] 6764 0
Auckland, Christchurch

Funding & Sponsors
Funding source category [1] 290957 0
Commercial sector/Industry
Name [1] 290957 0
AFT pharmaceutical Ltd
Address [1] 290957 0
Level 1, 129 Hurstmere Road, takapuna, Auckland, 0622
Country [1] 290957 0
New Zealand
Primary sponsor type
Commercial sector/Industry
Name
AFT pharmaceuticals Ltd
Address
Level 1, 129 Hurstmere Road, Takapuna, Auckland, 0622
Country
New Zealand
Secondary sponsor category [1] 289781 0
None
Name [1] 289781 0
Address [1] 289781 0
Country [1] 289781 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292555 0
Health and Disability Ethics Committees
Ethics committee address [1] 292555 0
Health and Disability Ethics Committees
Ministry of Health
C/- MEDSAFE, Level 6, Deloitte House
10 Brandon Street
PO Box 5013
Wellington
6011
Ethics committee country [1] 292555 0
New Zealand
Date submitted for ethics approval [1] 292555 0
26/03/2014
Approval date [1] 292555 0
13/05/2015
Ethics approval number [1] 292555 0
Ethics committee name [2] 295968 0
The Royal Children Hospital Melbourne, Research Ethtics and Governance
Ethics committee address [2] 295968 0
50 Flemington Road Parkville Victoria 3052 Australia
Ethics committee country [2] 295968 0
Australia
Date submitted for ethics approval [2] 295968 0
08/10/2015
Approval date [2] 295968 0
15/02/2016
Ethics approval number [2] 295968 0
HREC/15/RCHM/75

Summary
Brief summary
The primary purpose of this study is to define the PK profile of the Maxigesic oral suspension plus the clinical efficacy and safety of the high dose and low dose groups.

The other purpose of the study is to define the concentration-response relationship for the high dose and low dose of Maxigesic oral suspension
Trial website
NA
Trial related presentations / publications
NA
Public notes
NA

Contacts
Principal investigator
Name 55914 0
Prof Brian Anderson
Address 55914 0
AUCKLAND HOSPITAL
Level 1, Room 599-12081
PARK RD
Auckland 1023
GRAFTON
New Zealand
Country 55914 0
New Zealand
Phone 55914 0
+64 9 923 9300
Fax 55914 0
Email 55914 0
b.anderson@auckland.ac.nz
Contact person for public queries
Name 55915 0
Prof Brian Anderson
Address 55915 0
AUCKLAND HOSPITAL
Level 1, Room 599-12081
PARK RD
Auckland 1023
GRAFTON
New Zealand
Country 55915 0
New Zealand
Phone 55915 0
+64 9 923 9300
Fax 55915 0
Email 55915 0
b.anderson@auckland.ac.nz
Contact person for scientific queries
Name 55916 0
Dr Hartley Atkinson
Address 55916 0
AFT Pharmaceuticals Ltd, Level 1, 129 Hurstmere Road, Takapuna, Auckland, 0622
Country 55916 0
New Zealand
Phone 55916 0
+ 64 9 488 0232
Fax 55916 0
Email 55916 0
hartley@aftpharm.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
Have study results been published in a peer-reviewed journal?
Yes
Journal publication details
Publication date and citation/details [1] 852 0
Analgesic effectiveness, pharmacokinetics, and safety of a paracetamol/ibuprofen fixed-dose combination in children undergoing adenotonsillectomy: A randomized, single-blind, parallel group trial. Playne R, Anderson BJ, Frampton C, Stanescu I, Atkinson HC., Paediatr Anaesth. 2018 Dec;28(12):1087-1095. doi: 10.1111/pan.13517. Epub 2018 Oct 29.

Attachments [1] 852 0
Publication date and citation/details [2] 872 0
Acetaminophen, ibuprofen, and tramadol analgesic interactions after adenotonsillectomy.
Hannam JA, Anderson BJ, Potts A., Paediatr Anaesth. 2018 Oct;28(10):841-851. doi: 10.1111/pan.13464. Epub 2018 Aug 16.
Attachments [2] 872 0
Other publications
Have study results been made publicly available in another format?
No
Results – basic reporting
Results – plain English summary
This fixed dose combination (paracetamol 32 mg/mL + ibuprofen 9.6 mg/mL oral suspension) is safe to provide comparable pain relief at two different dose regimen ((Higher dose: paracetamol 15 mg/kg + ibuprofen 4.5 mg/kg, Lower dose: paracetamol 12 mg/kg + ibuprofen 3.6 mg/kg) among children aged from 2-12 years old following their tonsillectomy surgery.