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Trial registered on ANZCTR


Registration number
ACTRN12616000399493p
Ethics application status
Submitted, not yet approved
Date submitted
22/03/2016
Date registered
29/03/2016
Date last updated
28/11/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
The safety and efficacy of intranasal ketamine delivery for sedation of children in the emergency department. Is a needle-free approach to the care of children in the emergency department, practical and attainable?
Scientific title
Ketamine Intranasal Delivery in the Emergency Room: A multicentre randomised controlled trial of Intranasal(IN) versus Intravenous(IV)/Intramuscular(IV) ketamine for paediatric sedation in the Emergency Department. Is a totally needle-free approach feasible?
Secondary ID [1] 288764 0
NONE
Universal Trial Number (UTN)
Trial acronym
KINDER
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Sedation procedures in children 298012 0
Condition category
Condition code
Anaesthesiology 298172 298172 0 0
Other anaesthesiology

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a comparative study of intranasal (spray inhaled through the nose) to intramuscular/intravenous (injection into the muscle or vein) delivery of ketamine to children for procedural sedation.
Intranasal (N)
IN ketamine 10mg/kg, should be given in a staged and titrated fashion as outlined below. Doses inconsistent with this protocol will be considered protocol violations.
1. 10 minutes before ready to initiate procedure:
2.5mg/kg (0.025mL/kg Ketalar (registered trade name of ketamine) right/left nostril via Mucosal atomising device (MAD)
AND
2.5mg/kg (0.025mL/kg Ketalar other nostril via MAD
Total initial dose = 5mg/kg
2. Assess level of sedation after 2 minutes from initial dose (8 minutes before procedure expected to begin)
3. If initial 5mg/kg dose of sedation is considered insufficient to initiate procedure at this point, further IN doses can be titrated up to total initial load of 10mg/kg to achieve adequate dissociation/sedation to initiate procedure. Do this by alternating further doses of 2.5mg/kg between nostrils:
2.5mg/kg (0.025mL/kg Ketalar right/left nostril via MAD
AND/OR
2.5mg/kg (0.025mL/kg Ketalar other nostril via MAD
If 10mg/kg is reached and sedation is still insufficient to allow initiation of procedure 15 minutes after the first intranasal dose was administered, this shall be considered failed IN sedation and an IV cannula should be placed to allow titrated 0.25-0.5mg/kg doses of IV ketamine to achieve adequate sedation. The incidence with which this occurs shall impact the needle-free outcome.
For a prolonged procedure after successful initiation, repeated IN doses of 2.5mg/kg can be given to alternating nostrils 5 to 10 minutely.
The participants level of sedation will be deterined using the FLACC scale (face,legs,acitvity,cry and consolibilty scale), and discussed between the treating doctor and the senior consultant over-viewing the procedure.
It should be emphasised that while it may take longer to titrate the dose via the IN route compared with the IV route, this can be performed by the sedationist while the proceduralist finalises readiness for the procedure. It is anticipated that this longer titration period, if it occurs, shall be offset by the time saved by obviating IV.
The observation Nurse will be recording all data during the procedure, including baseline observations, indication for procedure, pain scores, fasting status, medication dosing, and 5minutely FLACC scores post initial medication administration.
Intervention code [1] 294212 0
Treatment: Drugs
Comparator / control treatment
Usual Care IV/IM (U)
In keeping with this trial being a practical study of a novel needle-free approach versus the range of current needle-based approaches, For patients randomised to the U arm clinicians will be free to choose either IV or IM routes and will also be free to choose the dose of ketamine administered by either of these routes.
For the U group, no recommendations shall be made about the timing of administering the drug in relation to performance of the procedure. No recommendations will be made regarding when or how to obtain IV access if this route is chosen.
Recommendations regarding dosing shall be made but not mandated:
Intramuscular route chosen
Recommended dose: 4-5 mg/kg IM ketamine; given as single dose into anterolateral thigh as soon as treating clinician/s ready to initiate sedation/procedure.
Child needs to be adequately restrained to ensure correct intramuscular administration.
If this single initial IM dose remains ineffective to initiate the procedure at 15 minutes post administration, or if a prolonged procedure requires top up doses, an IV cannula should be placed and titrated further 0.25-0.5mg/kg doses of IV ketamine should be given to achieve adequate sedation.
Intravenous route chosen
Recommended dose: 1.0-2.0 mg/kg IV ketamine (total initial dose); given by slow IV push of titrated doses (e.g. 0.5mg/kg) over 1-2 minutes as soon as the treating clinician/s are ready to initiate sedation/procedure
If further or top up doses are required to achieve or maintain sedation, then it is recommended that this occur via 0.25-0.5mg/kg doses of IV ketamine
Control group
Active

Outcomes
Primary outcome [1] 297694 0
Sedation efficacy/adequacy for procedure
2 Minutes post medication administration, the sedation score will be assessed using the FLACC scale (face, legs, activity. cry, consolability). If sedation is inadequate - a secondary dose can be given with re-assessment required.
If the patients sedation remains inadequate, this will be highlighted as a failed treatment. The patients care will be escalated at the discretion of the senior Medical office (Eg: utilisation of IM/IV Ketamine - though no data will be collected)
Timepoint [1] 297694 0
2 minutes post first medication administration and again 2 minutes post second medication administration
Secondary outcome [1] 321895 0
A composite of side effects 'yes' or 'no' out of 9, including; significant non-purposeful movements, involuntary eye movements, visual disturbance, hypersalivation not requiring significant intervention, vomitting during the period of sedation, intermittent throat spasm not requiring intervention, increased heart rate greater than 20beats per minute, increased systolic blood pressure greater than 20mmHg, or persistent balance effects).
These will be assessed through observation of the individual by clinical staff, observation of the individual by the parent/caregiver, and observation of the continuous screen monitoring of heart rate and blood pressure .
Timepoint [1] 321895 0
this will be assessed during the procedure and recovery stage, and again at the the 48 hour follow-up with the parent/caregiver
Secondary outcome [2] 321896 0
2. Parental/caregiver satisfaction with procedure will be assessed through the use of a 7 point likert scale. This will be assessed during the recovery stage of the procedure and again between 48 and 96 hours after the procedure, by phone call (This allows for research assistants to return to work, ie: long weekends),

Timepoint [2] 321896 0
during the recovery stage and again between 48 and 96 hours after the procedure, by phone call (This allows for research assistants to return to work, ie: long weekends),
Secondary outcome [3] 321898 0
Physician satisfaction regarding; the participants level of sedation, adequacy to complete the procedure, the route of administration, timeliness of the procedure, and willingness to use the same route again. These will be assessed using a 7 point likert scale.
Timepoint [3] 321898 0
These will be assessed during the recovery stage of the procedure for each participant
Secondary outcome [4] 321901 0
Requirement for IV cannulation during IN sedation not otherwise required for expected clinical course.
That is, requirement for cannulation to either manage complications of IN sedation or to achieve adequate sedation with IV top up ketamine doses. This will provide evidence of the proportion of paediatric emergency sedations that can be performed entirely needle-free.
Indication of Intravenous catheter or intraosseous insertion is on the medication dosing page of the case report form with yes or no tick boxes. If yes, the data collector is then prompted to indicate the reasoning for insertion (inadequate sedation, management of complications or care unrelated to the sedation).
Timepoint [4] 321901 0
Duration of the procedure
Secondary outcome [5] 321903 0
Time from triage to procedure complete - this will be assessed through a retrospective review of medical records.
Timepoint [5] 321903 0
between 48 and 96 hours after the procedure, by phone call (This allows for research assistants to return to work, ie: long weekends),
Secondary outcome [6] 321906 0
Emergency Department Length of Stay. A retrospective review of medical records.
Timepoint [6] 321906 0
between 48 and 96 hours after the procedure, (This allows for research assistants to return to work, ie: long weekends),
Secondary outcome [7] 322156 0
Comparison of minor adverse effects out of 2, between Intranasal and Intravenous/intramuscular delivery; including unpleasant taste in mouth and burning nose during intranasal administration. This will be observed by the clinical staff of participant discomfort, or if the participant is able to vocalise the effects.
Timepoint [7] 322156 0
during the procedure
Secondary outcome [8] 322157 0
A composition of serious adverse effects compared between the intranasal and the intravenous/intramuscular deliveries, including; severe agitation or distress requiring resedation/complex management, advanced airway management, basic supportive airway assistance, aspiration, persistent throat spasm that requires intervention, prolonged episodes of not breathing requiring intervention, or severe physiological disturbance requiring intervention. this will be measured out of 8.
Timepoint [8] 322157 0
during the procedure and recovery stage

Eligibility
Key inclusion criteria
1. Child of aged between greater than or equal to 12 months and less than or equal to 11 years
2. Weight between greater than or equal to 10kg and less than or equal to 40kg; corresponding to 100-400mg IN ketamine
3. Considered by appropriately qualified senior treating clinician (FACEM or SMO) to have an indication for emergency department sedation
Minimum age
12 Months
Maximum age
11 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. IV cannula already in situ at time of consideration for recruitment; or required for non-sedation indications prior to initiation of the sedation
2. Any previous adverse reaction or allergy to ketamine or other components of Ketalar (registered trade name)
3. Past history of significant cardiac disease, especially pulmonary hypertension
4.American Society of Anaesthesiology Classification > 1
5. Predicted difficult bag-mask ventilation or laryngoscopy
6. Critical illness
7. Severe trauma
8. Procedure better managed in operating theatre
9. Communicating hydrocephalus or other pre-existing condition predisposing to raised intracranial pressure (head injury is not an exclusion criteria unless meeting definition of major trauma)
10. Disease of the nose, significant coryza or nasal discharge, nasal obstruction or other condition preventing effective administration by the IN route

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)
Once eligibility is confirmed and informed consent obtained; clinicians will open a sequentially numbered (randomised number) opaque envelope to reveal the patients allocated treatment group. Treating clinicians will be required to enter patient details onto the envelope prior to opening and obtaining the allocation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be via computerised random number generator in a 1:1 allocation ratio, stratified to painful/non-painful procedure to ensure both U and N groups will be balanced in regards to this potential confounding variable. The randomised number will be used to label an envelope containing the allocation.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2 / Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis
Data will be entered into an Excel spreadsheet, access to which will be available only to study investigators. Data will be stored in a safe and secure location. Data will be analysed using SPSS 22.0. Continuous variables will be tested for normality. Based on the outcome of the test, parametric Student’s T test or non-parametric Mann-Whitney test will be carried out to determine the differences in data. Categorical data will be analysed using the Chi-squared analysis. A p value < 0.05 will be considered statistically significant.
All data will be analysed on an intention to treat basis. Patients who withdraw or are lost to follow up will be regarded as treatment failures for data analysis purposes and analysed with imputed data.

The sample size calculation is based on the non-inferiority of IN Ketamine compared to standard treatment with regard to the binary outcome of procedural sedation adequacy, as defined above in section Data points to be collected. The non-inferiority design was favoured as it is thought that the delivery of procedural sedation using the IN route has significant advantages over the conventional routes to justify use if it is demonstrated to be non-inferior by the pre-specified margin. Existing literature suggests that the percentage of procedural sedation success in the Usual Care (U) arm will be within the range of 90-98%. Using an estimate of 95% success in the usual care arm in our trial, a 5% margin of non-inferiority, with a one sided alpha of 5% and 90% power we would require 326 participants per group or 652 in total.
Calculations performed on:
https://www.sealedenvelope.com/power/binary-noninferior/

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/08/2016
Actual
Date of last participant enrolment
Anticipated
31/08/2017
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
652
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 5450 0
The Townsville Hospital - Douglas
Recruitment hospital [2] 5451 0
Redcliffe Hospital - Redcliffe
Recruitment hospital [3] 5452 0
Hervey Bay Hospital - Pialba
Recruitment hospital [4] 5453 0
Bundaberg Hospital - Bundaberg
Recruitment postcode(s) [1] 12936 0
4810 - Townsville
Recruitment postcode(s) [2] 12937 0
4670 - Bundaberg
Recruitment postcode(s) [3] 12938 0
4020 - Redcliffe
Recruitment postcode(s) [4] 12939 0
4655 - Hervey Bay

Funding & Sponsors
Funding source category [1] 293138 0
Charities/Societies/Foundations
Name [1] 293138 0
Queensland Emergency Medicine Research Foundation
Country [1] 293138 0
Australia
Primary sponsor type
Hospital
Name
The Townsville Hospital and Health Service
Address
100 Angus-Smith Drive, Douglas, Qld, 4814
Country
Australia
Secondary sponsor category [1] 291934 0
None
Name [1] 291934 0
n/a
Address [1] 291934 0
n/a
Country [1] 291934 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 294635 0
Children's Health Queensland Hospital and Health Service Human Research Ethics Committee
Ethics committee address [1] 294635 0
Ethics committee country [1] 294635 0
Australia
Date submitted for ethics approval [1] 294635 0
07/03/2016
Approval date [1] 294635 0
Ethics approval number [1] 294635 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes
Attachments [1] 816 816 0 0
/AnzctrAttachments/370334-24.02.16 KINDER Protocol version 2.0.pdf

Contacts
Principal investigator
Name 64394 0
Dr Luke Burman
Address 64394 0
The Townsville Hospital and Health Service
Emergency Department
100 Angus-Smith Drive, Douglas, Qld, 4814
Country 64394 0
Australia
Phone 64394 0
+617 44331111
Fax 64394 0
Email 64394 0
[email protected]
Contact person for public queries
Name 64395 0
Bethany Roche
Address 64395 0
The Townsville Hospital and Health Service
Emergency Department
100 Angus-Smith Drive, Douglas, QLD, 4814
Country 64395 0
Australia
Phone 64395 0
+61437028839
Fax 64395 0
Email 64395 0
[email protected]
Contact person for scientific queries
Name 64396 0
Luke Burman
Address 64396 0
The Townsville Hospital and Health Service
Emergency Department
100 Angus-Smith Drive, Douglas, Qld, 4814
Country 64396 0
Australia
Phone 64396 0
+61432 472 287
Fax 64396 0
Email 64396 0
[email protected]

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No Supporting Document Provided



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