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Trial registered on ANZCTR


Registration number
ACTRN12616001213437
Ethics application status
Approved
Date submitted
29/08/2016
Date registered
1/09/2016
Date last updated
11/03/2019
Date data sharing statement initially provided
11/03/2019
Date results information initially provided
11/03/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Ondansetron to reduce vomiting in children receiving intranasal fentanyl and inhaled nitrous oxide for procedural sedation: a double blind, randomised placebo controlled trial
Scientific title
Ondansetron to reduce vomiting in children receiving intranasal fentanyl and inhaled nitrous oxide for procedural sedation: a double blind, randomised placebo controlled trial
Secondary ID [1] 290039 0
None
Universal Trial Number (UTN)
U1111-1186-9946
Trial acronym
FON trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
vomiting 300085 0
sedation 300086 0
Condition category
Condition code
Anaesthesiology 299973 299973 0 0
Other anaesthesiology
Injuries and Accidents 299978 299978 0 0
Other injuries and accidents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Single-dose of study drug (Ondansetron vs Placebo syrup) by mouth, 30 minutes prior to procedural sedation. The following weight-based dosing will be used:
15-30kg = 5 ml of study drug (Ondansetron 4 mg or Placebo)
over 30 kg = 10 ml of study drug (Ondansetron 8 mg or Placebo)
At the time of randomisation, the investigator will access the study drug supply in the paediatric emergency department and dispense to the participant the next available box containing the appropriate weight-based dose. A research assistant may complete this task as long as it is counter-signed by a medically qualified staff.
Intervention code [1] 295765 0
Treatment: Drugs
Comparator / control treatment
Placebo syrup with the same appearance, taste and smell as the Ondansetron syrup.
Control group
Placebo

Outcomes
Primary outcome [1] 299457 0
Incidence of vomiting from beginning of procedural sedation with intranasal fentanyl and nitrous oxide until discharge from the paediatric emergency department or within one hour from the procedure (whichever comes first). This outcome will be recorded on the case report form by the medical staff caring for the participant during the emergency visit.
Timepoint [1] 299457 0
From beginning of procedure, defined as time of nitrous oxide mask application, until discharge from the paediatric emergency department or within one hour from the procedure (whichever comes first).
Secondary outcome [1] 327212 0
Number of vomits during procedural sedation
This outcome will be recorded on the case report form by the medical staff caring for the participant during the emergency visit.
Timepoint [1] 327212 0
Procedure time, defined as beginning with nitrous oxide mask application and ending with mask removal or when the child does not appear sedated, whichever comes latest.
Secondary outcome [2] 327213 0
Vomiting in the paediatric emergency department after procedural sedation
This outcome will be recorded on the case report form by the medical staff caring for the participant during the emergency visit.
Timepoint [2] 327213 0
From end of procedure until discharge from the paediatric emergency department
Secondary outcome [3] 327214 0
Vomiting after discharge
This outcome will be assessed with a follow-up phone call within a week of enrolment.
Timepoint [3] 327214 0
From discharge from the paediatric emergency department to 24 hours after the start of procedural sedation
Secondary outcome [4] 327215 0
Retching during procedural sedation
This outcome will be recorded on the case report form by the medical staff caring for the participant during the emergency visit.
Timepoint [4] 327215 0
Procedure time, defined as beginning with nitrous oxide mask application and ending with mask removal or when the child does not appear sedated, whichever comes latest.
Secondary outcome [5] 327216 0
Duration of procedural sedation
This outcome will be recorded on the case report form by the medical staff caring for the participant during the emergency visit.
Timepoint [5] 327216 0
Procedure time, defined as beginning with nitrous oxide mask application and ending with mask removal or when the child does not appear sedated, whichever comes latest.
Secondary outcome [6] 327217 0
Procedure abandonment
This outcome will be recorded on the case report form by the medical staff caring for the participant during the emergency visit.
Timepoint [6] 327217 0
Procedure time, defined as beginning with nitrous oxide mask application and ending with mask removal or when the child does not appear sedated, whichever comes latest.
Secondary outcome [7] 327218 0
Adverse events associated with procedural sedation.
This outcome will be recorded on the case report form by the medical staff caring for the participant during the emergency visit. When an adverse event is reported in the case report form, a member of the research team will review the participant's electronic medical record to corroborate the event.
Possible adverse events include:
a. oxygen desaturation: oxygen desaturation and one or more interventions are performed with the intention of improving the oxygen saturation
b. apnoea: cessation or pause of ventilatory effort and one or more interventions are performed with the intention of stimulating or assisting ventilation
c. laryngospasm: partial or complete upper airway obstruction, with oxygen desaturation caused by involuntary and sustained closure of the vocal cords and is not relieved by routine airway repositioning manoeuvers, suctioning, or insertion of a nasal or oral airway
d. pulmonary aspiration: suspicion or confirmation of oropharyngeal or gastric contents in the trachea during the sedation or physiologic recovery phase and the appearance of respiratory signs and symptoms that were not present before the sedation
e. bradycardia: pulse rate decreasing 2 standard deviations below normal for age as described by the electronic medical record
f. hypotension: mean blood pressure less than the fifth percentile for age, as defined by the electronic medical record
Timepoint [7] 327218 0
Procedure time, defined as beginning with nitrous oxide mask application and ending with mask removal or when the child does not appear sedated, whichever comes latest.
Secondary outcome [8] 327219 0
Parental importance and value put on prevention of vomiting using a survey specifically designed for this study
Timepoint [8] 327219 0
Survey administered once within one week of discharge from the paediatric emergency department
Secondary outcome [9] 327220 0
Parental satisfaction using a survey specifically designed for this study
Timepoint [9] 327220 0
Survey administered once within one week of discharge from the paediatric emergency department
Secondary outcome [10] 328575 0
Incidence of vomiting during procedural sedation with intranasal fentanyl and nitrous oxide. This outcome will be recorded on the case report form by the medical staff caring for the participant during the emergency visit.
Timepoint [10] 328575 0
Procedural sedation begins on application of the nitrous oxide mask and ends with mask removal or when the child does not appear sedated, whichever comes latest.

Eligibility
Key inclusion criteria
1. Be aged from 3 years to 18 years
2. Weight equal or greater than 15 kg
3. Planned procedural sedation with the combination of intranasal fentanyl and nitrous oxide
4. Have written informed consent provided by a parent or legal guardian. The participant may
also provide consent if he/she is deemed competent.
Minimum age
3 Years
Maximum age
18 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Contraindication to receiving intranasal fentanyl: opioid allergy and acute/chronic nasal
problems
2. Contraindication to receiving nitrous oxide as per institutional sedation manual
3. Contraindication to receiving ondansetron or placebo: known arrhythmia, use of QT-
prolonging drugs or allergy to any component of the ondansetron or placebo syrups
4. Cardiorespiratory instability
5. Decreased level of consciousness
6. Concomitant head injury
7. Planned use of additional sedatives

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)
Sequentially numbered syringes containing the study drug (ondansetron or placebo) will be identical in nature. Paediatric emergency staff assessing participants for eligibility will have no foreknowledge of treatment assignment, as the randomisation schedule will only be known by the independent statistician and the study pharmacist.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be randomised in a 1:1 ratio to one of two treatment arms: ondansetron or placebo. Randomisation will be stratified by weight (15-30 kg and >30 kg). An independent statistician will generate the randomisation schedule using block randomisation with variable block sizes to maintain approximate balance between treatment arms.
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 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis
The primary outcome is the proportion of participants experiencing vomiting during PSA with INF and N2O. There is currently only one report on the rate of vomiting associated with the administration of INF and N2O. In this report of 41 children receiving INF and N2O at the RCH, the vomiting rate was 19.5% (95% exact binomial CI [8.8%, 34.9%]). In a separate study we found an incidence of vomiting of 27.6% in 29 children (95% exact binomial CI [12.7%,47.2%]) undergoing PSA with INF and N2O at this institution. Based on clinical opinion, we propose that reducing the incidence of vomiting to 10% would be a clinically significant improvement and one that would potentially change practice. Assuming conservatively, that 20% of children in the placebo group will vomit during PSA, we therefore power our study to identify an absolute reduction of 10% (from 20% to 10%). A similar reduction in the incidence of vomiting, from 18.9% to 7.8%, was previously found in a trial where ondansetron was administered to children undergoing PSA with ketamine. Assuming 20% vomit in the placebo group, a sample size of 398 patients would be required in order for us to detect a reduction to 10% or lower (i.e. odds ratio of 0.44 or number needed to treat of 10) with 80% power, based on a two-sided test with type 1 error of 0.05. We therefore aim to recruit 442 participants to allow for 10% loss to follow-up.

Baseline characteristics will be compared between the ondansetron and placebo groups using summary statistics (means and standard deviations for continuous variables and numbers and percentages for categorical variables).

The primary outcome of the incidence of vomiting during PSA will be presented as the number and proportion in each treatment group, with a comparison between the groups presented as a difference in proportions and as an odds ratio from a logistic regression model adjusted for weight (15-30 kg and >30 kg), with a 95% confidence interval (CI) and p-value (primary objective). In addition, we will present the results as Number-Needed-to-Treat (NNT) and its 95% CI.

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] 6556 0
The Royal Childrens Hospital - Parkville
Recruitment postcode(s) [1] 14154 0
3052 - Parkville

Funding & Sponsors
Funding source category [1] 294410 0
Other Collaborative groups
Name [1] 294410 0
Murdoch Children’s Research Institute
Address [1] 294410 0
Emergency Research, Murdoch Children's Research Institute
The Royal Children's Hospital
50 Flemington Rd
Parkville
Victoria 3052; Australia
Country [1] 294410 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Murdoch Children’s Research Institute
Address
Emergency Research, Murdoch Children's Research Institute
Royal Children's Hospital
50 Flemington Rd
Parkville
Victoria 3052; Australia
Country
Australia
Secondary sponsor category [1] 293258 0
None
Name [1] 293258 0
Address [1] 293258 0
Country [1] 293258 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295829 0
The Royal Children’s Hospital Melbourne Human Research Ethics Committee (HREC)
Ethics committee address [1] 295829 0
The Royal Children's Hospital
50 Flemington Rd
Parkville
Victoria 3052; Australia
Ethics committee country [1] 295829 0
Australia
Date submitted for ethics approval [1] 295829 0
08/06/2016
Approval date [1] 295829 0
11/08/2016
Ethics approval number [1] 295829 0
36174A

Summary
Brief summary
We set out to assess the impact of ondansetron on the incidence of vomiting in children undergoing procedural sedation and analgesia (PSA) with the combination of intranasal fentanyl (INF) and inhaled nitrous oxide (N2O) compared with placebo. We hypothesize that ondansetron can significantly decrease the rate of vomiting associated with the combination of INF and N2O. Currently, there exists no report of any strategy to reduce the occurrence of vomiting in patients receiving INF and N2O.

This is a phase III, double-blinded, placebo-controlled superiority trial of ondansetron for prevention of vomiting associated with PSA with the combination of INF and N2O. Participants will be randomized to receive one dose of ondansetron oral syrup (4 mg for patients 15-30 kg; 8 mg for patients >30 kg) or matched placebo during PSA.

The treatment period will be limited to the participants’ emergency visit requiring PSA. The follow-up period will be of a maximum of one week (aiming for less than 72 hours) for each individual, ending at the time of the phone follow-up.

The primary outcome is to determine if ondansetron decreases the incidence of vomiting during PSA with the combination of INF and N2O in children aged between 3 and less than 18 years compared with placebo. Secondary outcomes are to determine the effect of ondansetron compared with placebo on:
a. Number of vomits during PSA
b. Vomiting in the PED after PSA
d. Vomiting within 24 hours of the start of the procedure
c. Retching during PSA
d. Procedure duration
e. Procedure abandonment
f. PSA-associated adverse events during the emergency visit
g. To explore parental satisfaction
h. To explore value parents put on vomiting
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 68638 0
Dr Sandy Hopper
Address 68638 0
The Royal Children's Hospital
50 Flemington Rd
Parkville
Victoria 3052; Australia
Country 68638 0
Australia
Phone 68638 0
+61417177767
Fax 68638 0
+61393455938
Email 68638 0
sandy.hopper@rch.org.au
Contact person for public queries
Name 68639 0
Dr Emmanuelle Fauteux-Lamarre
Address 68639 0
The Royal Children's Hospital
50 Flemington Rd
Parkville
Victoria 3052; Australia
Country 68639 0
Australia
Phone 68639 0
+61452626556
Fax 68639 0
+61393455938
Email 68639 0
emmanuelle.fauteux-lamarre@rch.org.au
Contact person for scientific queries
Name 68640 0
Dr Emmanuelle Fauteux-Lamarre
Address 68640 0
The Royal Children's Hospital
50 Flemington Rd
Parkville
Victoria 3052; Australia
Country 68640 0
Australia
Phone 68640 0
+61452626556
Fax 68640 0
+61393455938
Email 68640 0
emmanuelle.fauteux-lamarre@rch.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
We have not planned to make data publicly available
What supporting documents are/will be available?
No other documents available
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
No
Results – basic reporting
Results – plain English summary