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Trial registered on ANZCTR


Registration number
ACTRN12617001490369
Ethics application status
Approved
Date submitted
16/10/2017
Date registered
23/10/2017
Date last updated
25/07/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A pilot randomised open-label taste-testing study to evaluate the acceptability of chocolate-based tramadol in children
Scientific title
Palatable and chewable tramadol chocolate-based tablets for pain management in paediatric patients
Secondary ID [1] 292991 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pain management in relation to surgery 304899 0
Condition category
Condition code
Anaesthesiology 304221 304221 0 0
Anaesthetics
Anaesthesiology 304222 304222 0 0
Pain management

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
After approval from the treating anaesthetist and voluntary informed consent by the parent/guardian, the participants will be randomised by computer generated block randomisation to receive either the comparator formulation (n of 75) or the Chocolate-based tramadol oral Delivery System CDS tablet (n of 75) on a 1 mg/kg dose basis by mouth as prescribed by the treating anaesthetist. The comparator formulation is a 5 mg/ml tramadol oral liquid prepared by reconstituting the commercial 50 mg tramadol capsules in water as per recommendations issued at The Royal Children’s Hospital in Melbourne. The drug administration is just for the one administration timepoint (prior to surgery). No additional prescriptions of study medication will be given after this time point.

Compliance of taking the drug as well as a scale scored by the child and the parent on how much he/she likes/dislikes the sample will be recorded.
If the child spits out the dose immediately, the treating anaesthetist will decide in line with current routine management, whether a second dose is required. If the second dose is recommended, the treating anaesthetist along with the parent/child will decide upon the same dosage form or the alternative form.
The pharmacokinetic parameters of the chocolate-based tramadol tablet and the compounded tramadol compararot solution will be evaluated using a validated HPLC assay and a flexible blood sampling protocol.
Intervention code [1] 299390 0
Treatment: Drugs
Comparator / control treatment
The comparator formulation is a 5 mg/ml tramadol oral liquid prepared by the pharmacy team by reconstituting the commercial 50 mg tramadol capsules in water as per recommendations issued at The Royal Children’s Hospital in Melbourne.
This will be administered into the mouth.
Control group
Active

Outcomes
Primary outcome [1] 303664 0
Mean visual analogue scale scores from the participants and their parents for acceptance (Composite Outcome)
Timepoint [1] 303664 0
Day of surgery; at time of administration of study drug.
The administration of each study drug to each participant will be witnessed by a study team member and questions with both the participant and the parents on acceptance will be documented on a study data sheet.
Primary outcome [2] 303665 0
Relative bioavailability between tramadol hydrochloride Chocolate-based oral Delivery System tablet and the 5 mg/ml tramadol hydrochloride oral liquid prepared using the commercial tramadol hydrochloride 50 mg capsule
Timepoint [2] 303665 0
Day of surgery blood sample analysis.
The first sample will be collected as soon as possible after the child is asleep (approximately 30 minutes or slightly earlier after taking tramadol). The second and third samples will be collected between 45-60 minutes and 90-120 minutes respectively. The fourth sample will be taken as late as possible (depending on planned discharge of patient and cannula patency) from 140-300 min.
Primary outcome [3] 303699 0
Mean visual analogue scale scores from the participants for taste
Timepoint [3] 303699 0
Day of surgery at time of administration.
The administration of each study drug to each participant will be witnessed by a study team member and questions with the participants on taste will be documented on a study data sheet.
Secondary outcome [1] 339811 0
Number/percentage of children who spat out the dose
Timepoint [1] 339811 0
Day of surgery; at time of administration of study drug.
The administration of each study drug to each participant will be witnessed by a study team member and documented on a study data sheet.
Secondary outcome [2] 339812 0
Number/percentage of children willing to take the alternative treatment (i.e. chocolate based tramadol tablet or the compounded tramadol solution)
Timepoint [2] 339812 0
Day of surgery; at time of administration of study drug
The administration of each study drug to each participant will be witnessed by a study team member and documented on a study data sheet.
Secondary outcome [3] 339813 0
Number/percentage of children willing to consume the assigned dosage for the second time
Timepoint [3] 339813 0
Day of surgery; at time of administration of study drug
The administration of each study drug to each participant will be witnessed by a study team member and documented on a study data sheet.
Secondary outcome [4] 339814 0
Number/percentage of adverse reactions which could include PONV, dizziness, nausea or vomiting, sweating, change in bowel habits, confusion, sleep disturbance, blurred vision, sedation, hallucinations or seizures. This will be documented from the review of the patient post administration of the study medication and from a review of the medical notes.
Timepoint [4] 339814 0
Day of surgery; at time of administration of study drug, during their hospital stay and in the 24 hour period following administration. Participants will have a follow up phone call within 5 days of day of surgery.

Eligibility
Key inclusion criteria
Male or female, 3 to 16 years of age
Treating anaesthetist considering patient suitable for pre-procedural tramadol
Obtained informed parental or guardian consent and child assent where appropriate
Minimum age
3 Years
Maximum age
16 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Known allergy to chocolate (chocolate base does not contain nuts)
Known allergy/intolerance to tramadol or opioids
Unable to understand the information sheet and the consent form
Patient taking medication known to interact with tramadol (e.g. serotonergic agents, warfarin, ketoconazole)
Known significant renal or hepatic impairment
Known seizure disorder or epilepsy
Participants undergoing surgeries that remove the tonsils or adenoids.
Obese (as detailed by a BMI percentile above the 95th)
Known severe obstructive sleep apnoea as documented by an overnight sleep study
Known severe respiratory disease with significant impact on daily life

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)
All patients will be recruited at the pre-anaesthetic review. Only patients who meet the inclusion criteria for the study will be enrolled and only after informed consent is given voluntarily by the parent/guardian and by the patient if appropriate.
The patients will be randomised by computer generated block randomisation. Following written informed consent, the participant will be assigned the next available Participant Number. The Participant Number will correspond to a numbered randomisation envelope. The randomisation is concealed in the closed opaque envelope and will only be opened by the research team member at the time of enrolment. The participant number will be used to identify the patient for the duration of the study.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computer generated block randomisation
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Sample Size
This pilot study will apply the Wilcoxon-Mann-Whitney statistical test to test our hypothesis. We estimate that, with the effect size d=0.5 and alpha=0.05, we will have 80% power to detect a difference with 67 children in each group (G * Power 3.1). Given that some children may drop out of this study, we will recruit 75 children in each group.
Palpability assessment
Taste data will be analysed using the non-parametric Mann-Whitney test and 2-tailed unpaired t-test. The gender distribution and the participant’s willingness of taking the second dose will be analysed using 2-tailed Chi-square test. All statistical analyses will be performed with PRISM 6 for Mac (GraphPad software). A P value <0.05 is considered statistically significant.
Pharmacokinetic assessment
A simulation based method was used to determine the power to achieve adequate evidence of equivalent relative bioavailability. Specifically, 1,000 datasets of 150 patients each were simulated using literature values for tramadol with a blood sampling regimen based on that which was able to be obtained in a similar recent study of midazolam (average of 2.5 samples/ patient).
Each dataset was then analysed within NONMEM and the 90% CI for the ratio parameter obtained. Models for which this fell within the range of 0.80 to 1.25, in accordance with FDA and EMA guidance, were counted as successful. Given even a true ratio did not achieve a power of 80% (expected to be lower than that achieved with midazolam given tramadol has a longer half-life), simulations were repeated with the final sample between 2-4 hours after dose. With this additional sample, there was 80% power for true ratios between 0.94 and 1.06. Reducing the patient number to 100 with the same sampling schedule resulted in inadequate power.

Recruitment
Recruitment status
Recruiting
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)
WA
Recruitment hospital [1] 9116 0
Princess Margaret Hospital - Subiaco
Recruitment hospital [2] 9117 0
Perth Children's Hospital - Nedlands
Recruitment postcode(s) [1] 17616 0
6008 - Subiaco
Recruitment postcode(s) [2] 17617 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 297617 0
Charities/Societies/Foundations
Name [1] 297617 0
ANZCA - Australia New Zealand College of Anaesthetists
Address [1] 297617 0
Australian and New Zealand College of Anaesthetists
ANZCA House,
630 St Kilda Road,
Melbourne, Victoria 3004,
Country [1] 297617 0
Australia
Funding source category [2] 297764 0
Hospital
Name [2] 297764 0
Telethon-Perth Children's Hospital Research Fund
Address [2] 297764 0
Department of Health
189 Royal St,
East Perth
WA 6004
Country [2] 297764 0
Australia
Primary sponsor type
Hospital
Name
Princess Margaret Hospital
Address
Roberts Road
Subiaco
WA 6008
Country
Australia
Secondary sponsor category [1] 296632 0
Individual
Name [1] 296632 0
Prof Britta von Ungern-Sternberg
Address [1] 296632 0
Department of Anaesthesia and Pain Management
Princess Margaret Hospital
Roberts Road
Subiaco
WA 6008
Country [1] 296632 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298707 0
Children and Adolescent Health Service Human Research Ethics Committee
Ethics committee address [1] 298707 0
Roberts Road
Subiaco
WA 6008
Ethics committee country [1] 298707 0
Australia
Date submitted for ethics approval [1] 298707 0
18/04/2017
Approval date [1] 298707 0
26/09/2017
Ethics approval number [1] 298707 0
RGS0000000205

Summary
Brief summary
There is a limited number of strong pain relieving medications available for children. All have their own advantages and dis-advantages. For example, anti-inflammatories, like ibuprofen, are unsuitable for those with a bleeding risk and can cause kidney damage. Morphine like drugs come with the risk of slowing breathing and a fear of diversion for illegal use. Tramadol is a medicine that has been used safely for many years in both adults and children. Its advantage is that is has similar pain relieving power to morphine like drugs in the typical dose range, but because it works in a different way, it has much less ability to impair breathing.
Its main disadvantage in children is that the drug itself tastes very bitter. In adults, this is overcome by presenting the medication in capsules, so the drug is not released until it reaches the stomach. While there are some 82 registered products in Australia containing tramadol, none of them are licenced for use in children. To provide a suitable dose to small child, the standard adult dose capsule must be broken open, the drug dissolved in water, and the correct proportion given. This is cumbersome for parents, risks error in dosing and produces a horrible tasting solution that most children dislike.
There is one preparation available (although not licensed for use in children) of very concentrated oral drops, 1ml containing 100mg of drug, equal to 2 standard capsules. This is unsuitable for young children because the risk of overdose with such a concentrated solution is great, and has occurred with this formulation.
To make drugs more palatable to young children they are often dissolved in syrup, but this only masks the bitter taste to a degree and often involves adding artificial flavours and sweeteners. The pharmacy department at Princess Margaret hospital (PMH) in partnership with the Anaesthesiology, Pharmacology and Pharmacy Unit at the University of Western Australia has developed a novel chocolate sweet which can be used to mask the taste of bitter drugs. It has already been used successfully for other medications and found to be very acceptable to children. Using this delivery system has also given the ability to deliver a smaller defined dose, not previously available in Australia, which will allow easier and more reliable dosing in smaller children.
This study plans to test the chocolate tramadol tablet against the current broken-open capsule method of delivering tramadol in patients following minor to moderate operations at Princess Margaret Hospital. We will compare how the new “tablet” is tolerated, absorbed and if it is an effective pain reliever. Ultimately we hope to develop a new method to deliver tramadol so it can be more easily and safely be given to children.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 77966 0
Prof Britta von Ungern-Sternberg
Address 77966 0
Princess Margaret Hospital
Department of Anaesthesia and Pain Management
Roberts Road
Subiaco
WA 6008
Country 77966 0
Australia
Phone 77966 0
+61893408109
Fax 77966 0
+61893408755
Email 77966 0
britta.regli-vonungern@health.wa.gov.au
Contact person for public queries
Name 77967 0
Prof Britta von Ungern-Sternberg
Address 77967 0
Princess Margaret Hospital
Department of Anaesthesia and Pain Management
Roberts Road
Subiaco
WA 6008
Country 77967 0
Australia
Phone 77967 0
+61893408109
Fax 77967 0
+61893408755
Email 77967 0
britta.regli-vonungern@health.wa.gov.au
Contact person for scientific queries
Name 77968 0
Prof Britta von Ungern-Sternberg
Address 77968 0
Princess Margaret Hospital
Department of Anaesthesia and Pain Management
Roberts Road
Subiaco
WA 6008
Country 77968 0
Australia
Phone 77968 0
+61893408109
Fax 77968 0
+61893408755
Email 77968 0
Britta.Regli-VonUngern@health.wa.gov.au

No data has been provided for results reporting
Summary results
Not applicable