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Trial registered on ANZCTR


Registration number
ACTRN12615000225516
Ethics application status
Approved
Date submitted
24/02/2015
Date registered
10/03/2015
Date last updated
30/01/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
A pilot randomised open-label taste-testing study to evaluate the acceptability of chocolate-based midazolam in children
Scientific title
A study comparing taste and adherence to administration of a midazolam chocolate formulation compared to the standard hospital midazolam solution used as a premedication prior to general anaesthesia for surgical procedures in children aged 3 to 16 years of age.
Secondary ID [1] 286256 0
Nil Known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Children needing a sedating premedication prior to general anaesthesia for a surgical procedure 294308 0
Condition category
Condition code
Anaesthesiology 294636 294636 0 0
Anaesthetics

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
All participants will be recruited at the pre anaesthetic review prior to the procedure once the treating anaesthetist advises that the patient will be prescribed midazolam as a pre medication.
The participants will be randomised to receive either the chocolate tablet formulation of midazolam (5mg mini tablet with score lines for dose division) or the hospital standard IV solution of midazolam (5mg/ml injection Pfizer) by mouth as prescribed by treating anaesthetist. This injection solution is what is currenlty used clinically in the hospital and it is given by mouth. The dose of the midazolam to be administered will be determined by the treating anaesthetist based on the patients weight and clinical status.
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 time to onset of sedation (clinical effect of midazolam) will be also recorded.
The pharmacokinetic parameters of the chocolate-based midazolam tablet and the IV midazolam solution will be evaluated using a validated HPLC assay for midazolam and a flexible blood sampling protocol.
Intervention code [1] 291273 0
Treatment: Drugs
Comparator / control treatment
Comparator is the currently used hospital standard IV solution of midazolam (Pfizer). This will be administered into the mouth.
Control group
Active

Outcomes
Primary outcome [1] 294400 0
Mean visual analogue scale scores from the participants and their parents to evaluate taste adherence.
Timepoint [1] 294400 0
Recorded after administration of the midazolam.
Secondary outcome [1] 313195 0
Number of children who spat out the dose
Timepoint [1] 313195 0
Recorded at the time of the administration of the midazolam.
Secondary outcome [2] 313196 0
Number of children willing to take the alternative
Timepoint [2] 313196 0
Recorded at the time of the administration of the midazolam.
Secondary outcome [3] 313197 0
Number of children willing to consume the assigned dosage form again
Timepoint [3] 313197 0
Recorded at the time of the administration of the midazolam.
Secondary outcome [4] 313404 0
This study also aims to evaluate the pharmacokinetic parameters of the chocolate-based midazolam tablets in children.
Timepoint [4] 313404 0
The first sample will be collected as soon as possible after the child is asleep (approximately 30 minutes or slightly earlier after taking midazolam). The second and third samples will be collected between 45-60 minutes and 90-120 minutes respectively. The final sample will be collected as late as possible, before the procedure is completed.

Eligibility
Key inclusion criteria
Male or female, 3 to 16 years of age undergoing a wide range of surgical procedures requiring a general anaesthetic.
Treating anaesthetist consider that pre-procedural midazolam is required
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
Allergic to chocolate (chocolate base does not contain nuts)
Allergic to midazolam
Unable to understand the information sheet and the consent form

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 envelope and will only be opened by the administering nurse at the time of administration of the midazolam. 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
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. Given that some children may drop out of this study, we will recruit 75 children in each group.

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)
WA
Recruitment hospital [1] 3515 0
Princess Margaret Hospital - Subiaco
Recruitment postcode(s) [1] 9279 0
6008 - Subiaco

Funding & Sponsors
Funding source category [1] 290817 0
Charities/Societies/Foundations
Name [1] 290817 0
Princess Margaret Hospital Foundation
Address [1] 290817 0
68 Hay Street
Subiaco
WA 6008
Country [1] 290817 0
Australia
Funding source category [2] 293419 0
Other
Name [2] 293419 0
ANZCA - Australia New Zealand College of Anaesthetists
Address [2] 293419 0
Australian and New Zealand College of Anaesthetists
ANZCA House,
630 St Kilda Road,
Melbourne, Victoria 3004,
Australia.
Country [2] 293419 0
Australia
Primary sponsor type
Hospital
Name
Princess Margaret Hospital
Address
Roberts Road
Subiaco
WA 6008
Country
Australia
Secondary sponsor category [1] 289502 0
Individual
Name [1] 289502 0
Dr Laurence Cheung
Address [1] 289502 0
Princess Margaret Hospital
Roberts Road
Subiaco
WA 6008
Country [1] 289502 0
Australia
Secondary sponsor category [2] 289503 0
Individual
Name [2] 289503 0
Prof Britta Regli-Von Ungern-Sternberg
Address [2] 289503 0
Princess Margaret Hospital
Roberts Road
Subiaco
WA 6008
Country [2] 289503 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292441 0
Princess Margaret Hospital Ethics Committee
Ethics committee address [1] 292441 0
Roberts Road
Subiaco
WA 6008
Ethics committee country [1] 292441 0
Australia
Date submitted for ethics approval [1] 292441 0
06/10/2014
Approval date [1] 292441 0
01/04/2015
Ethics approval number [1] 292441 0
EP/2014102

Summary
Brief summary
To achieve the benefits of a medicine, the patient must be willing to take it in the correct amount at the appropriate time. Most medicines are not formulated for use in children. For those that are, few are considered sufficiently palatable. Lack of palatability can be attributed to poor taste and, for children below 6 years, the inability to swallow solid medicines, such as tablets.

Midazolam is a highly effective oral sedative and pre-procedural medicine for children and adolescents. The lack of an oral commercial product in Australia has led the local hospitals to administer midazolam injection solution which has a foul taste and is often rejected by the children. Inadequate sedation presents difficulties in children who are very anxious or uncooperative in the preoperative setting (e.g. children with autism). Uncooperative children have then to be held down and restrained for the induction of anaesthesia, which is traumatizing for the child and the family. In adolescents, this can also pose significant safety risks for the attending staff.

We believe that chocolate-based mini tablets can effectively provide palatable formulations for bitter drugs such as midazolam to assist clinicians achieve the desired therapeutic outcomes in paediatric patients.
The aims of this project are:
1. To evaluate the rate of acceptance of the chocolate-based midazolam tablets in children (age 3-16) required pre-procedural midazolam
2. To evaluate the pharmacokinetic prarameters of the chocolate-based midazolam tablets in children

We have developed prototype chocolate tablets measuring 0.5 x 1 x 0.5 cm that can mask the taste of the highly bitter drug. The aims of this project are to perform further clinical evaluations on these formulations to fully realise the potential of midazolam for preprocedural sedation and anxiolysis of sick children in WA.

This study will pave the way for the scaled up manufacture of chocolate-based midazolam tablets for use in WA paediatric hospital wards, and the adaptation of the chocolate base for the formulation of other bitter drugs (e.g. antibiotics). Pharmaceutically, the chocolate tablets, which are prepared without water, will provide more stable products for labile drugs than liquid mixtures. They are also more convenient and cheaper to store and transport than bulky liquid formulations.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 55290 0
Dr Laurence Cheung
Address 55290 0
Princess Margaret Hospital
Pharmacy Department
Roberts Road
Subiaco
WA 6008
Country 55290 0
Australia
Phone 55290 0
+61 8 9340 8206
Fax 55290 0
Email 55290 0
Laurence.Cheung@telethonkids.org.au
Contact person for public queries
Name 55291 0
Dr Laurence Cheung
Address 55291 0
Princess Margaret Hospital
Pharmacy Department
Roberts Road
Subiaco
WA 6008
Country 55291 0
Australia
Phone 55291 0
+61 8 9340 8206
Fax 55291 0
Email 55291 0
Laurence.Cheung@telethonkids.org.au
Contact person for scientific queries
Name 55292 0
Prof Britta Regli-von Ungern-Sternberg
Address 55292 0
Princess Margaret Hospital
Department of Anaesthesia and Pain Managment
Roberts Road
Subiaco
WA 6008
Country 55292 0
Australia
Phone 55292 0
+61 8 9340 8109
Fax 55292 0
Email 55292 0
Britta.Regli-VonUngern@health.wa.gov.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary