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Trial registered on ANZCTR


Registration number
ACTRN12618000429257
Ethics application status
Approved
Date submitted
4/03/2018
Date registered
26/03/2018
Date last updated
29/11/2018
Date data sharing statement initially provided
29/11/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A multicentre, randomised, non-inferiority trial of chewing gum versus ondansetron to treat postoperative nausea and vomiting in female patients after breast or laparoscopic surgery (The Chewy Trial)
Scientific title
A multicentre, randomised, non-inferiority trial of chewing gum versus ondansetron to treat postoperative nausea and vomiting in female patients after breast or laparoscopic surgery (The Chewy Trial)
Secondary ID [1] 294070 0
Nil
Universal Trial Number (UTN)
U1111-1209-4583
Trial acronym
The Chewy Trial (CHewing gum to treat post-operative nausea and Emesis in Women)
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Postoperative nausea and vomiting 306624 0
Condition category
Condition code
Anaesthesiology 305730 305730 0 0
Anaesthetics
Surgery 306094 306094 0 0
Other surgery

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
One stick of sugar-free peppermint-flavoured chewing gum (Wrigley’s Extra Sugarfree Gum, Wrigley Company) in the event of nausea, retching and/or vomiting occurring in the post anaesthesia care unit (PACU) after anaesthesia. Patients will be observed by a blinded observer who is a member of the study team. While in the PACU patients may spontaneously report nausea or be observed to retch or vomit. If patients do not spontaneously report nausea and are not observed to retch or vomit, they will be asked “Are you feeling sick?” every 15 minutes by the observer. If nausea, retching and/or vomiting are present the patient will be assessed for alertness using the Observer's Assessment of Alertness and Sedation (OAA/S) score. If the score is 5, the observer will leave the PACU, maintaining blinding to group allocation. The PACU nurse will then randomize the patient and administer the randomly allocated intervention. Fifteen minutes later, the chewing gum will be discarded (if applicable). The blinded observer will then return to the PACU to observe the patient continuously for retching or vomiting and to ask about nausea every 15 minutes until 2 hours after randomization. Rescue medication will be administered to patients who experienced a nausea score of moderate or severe for a period of >15 minutes, 2 or more episodes of retching or vomiting within 15 minutes, at patient request or at the discretion of the treating team any time from the administration of the randomised treatment to 2 hours later. The observer will be blind to the identity of each rescue medication given. Patients will be discharged from the PACU when they meet local discharge criteria. If the OAA/S score is <5, chewing gum will not be allowed. The patient will receive anti-emetic treatment at the discretion of the attending anaesthetist and will not be followed further. The number of consented patients who are not randomised will be reported, with reasons. Patients who are randomised to chewing gum but who do not chew it (for whatever reason) will receive ondansetron 4 mg IV (the first rescue treatment in the chewing gum group) and will continue in the study as part of the chewing gum intention-to-treat arm.
Intervention code [1] 300343 0
Treatment: Other
Intervention code [2] 300595 0
Treatment: Drugs
Comparator / control treatment
Ondansetron 4 mg, intravenously (IV) (once only)
Control group
Active

Outcomes
Primary outcome [1] 304807 0
Proportion of patients with complete cessation of nausea, retching and vomiting within 2 hours of administration (composite outcome), with no recurrence between cessation and 2 hours after administration, and no rescue medication between administration and 2 hours after administration (i.e. complete response). (Investigator direct observation for vomiting/nausea and direct interview for nausea using verbal descriptive scale)
Timepoint [1] 304807 0
Within 2 hours of administration of randomised intervention (nausea assessed every 15 minutes, with the primary timepoint at 2 hours).
Secondary outcome [1] 343253 0
Acceptability of randomised treatment to patients (5 point Likert scale)
Timepoint [1] 343253 0
15 minutes after administration of randomised treatment
Secondary outcome [2] 343254 0
Time to complete response (complete resolution of nausea, vomiting and/or retching),(measured by blinded investigator using investigator interview with binary question for nausea resolution)
Timepoint [2] 343254 0
Within 2 hours of administration of randomised intervention
Secondary outcome [3] 343255 0
Numbers of episodes of nausea, retching and/or vomiting in the PACU (composite outcome) (measured by blinded investigator interview)
Timepoint [3] 343255 0
Within 2 hours of administration of randomised intervention (total number of episodes of nausea, retching and/or vomiting within the 2 hour period)
Secondary outcome [4] 343256 0
Numbers of rescue treatments for PONV (measured by direct observation by blinded investigator using a study specific questionnaire present through PACU stay)
Timepoint [4] 343256 0
Within 2 hours of administration of randomised intervention
Secondary outcome [5] 343257 0
Duration of PACU stay (measured by direct observation by blinded investigator using a study specific questionnaire present through PACU stay)
Timepoint [5] 343257 0
At discharge from PACU
Secondary outcome [6] 343258 0
Quality of recovery (measured using the QOR-15 scale)
Timepoint [6] 343258 0
At 24 hours after randomisation or at discharge from hospital (whichever is sooner)
Secondary outcome [7] 343259 0
Duration of hospital stay (measured by blinded investigator using data linkage to medical records)
Timepoint [7] 343259 0
At discharge from hospital
Secondary outcome [8] 343260 0
Costs of randomised medications, rescue medications and hospital stay (measured by blinded investigator using study specific questionnaire)
Timepoint [8] 343260 0
At discharge from hospital
Secondary outcome [9] 343261 0
Willingness-to-pay for complete response (measured by blinded investigator using investigator interview using a study-specific questionnaire)
Timepoint [9] 343261 0
At 24 hours after randomisation or at discharge from hospital (whichever is sooner)
Secondary outcome [10] 344559 0
Functional health and wellbeing (using the SF-12 or SF-10 paediatric scale)
Timepoint [10] 344559 0
At 24 hours after randomisation or at discharge from hospital (whichever is sooner)
Secondary outcome [11] 344560 0
Safety outcomes: Swallowing of chewing gum, inhalation of chewing gum, unplanned overnight admission in scheduled day cases, unplanned intensive care unit admission, cardiovascular events, pulmonary events, wound events, death (measured by direct observation or data linkage to medical records by blinded investigator)
Timepoint [11] 344560 0
Safety outcomes occur between randomization and 24 h after randomization or hospital discharge (whichever is sooner)
Secondary outcome [12] 344784 0
Acceptability of randomised treatment to PACU nurses (5 point Likert scale)
Timepoint [12] 344784 0
15 minutes after administration of randomised treatment

Eligibility
Key inclusion criteria
Female patients aged 12 years or older, weight 30 kg or more, preoperative Apfel score 2-4, presenting for breast or laparoscopic surgery under volatile-based, general anaesthesia.
Minimum age
12 Years
Maximum age
No limit
Gender
Females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients having propofol-maintained general anaesthesia or inhalational induction without propofol co-induction, a contraindication to chewing gum, or any protocolised anti-emetic drug (prophylaxis, intervention or rescue), treatment with any of the study anti-emetic medications within 8 hours of induction of anaesthesia or planned post operative ventilation.

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)
Web-based randomisation service
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computer generated randomisation sequence
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
The statistical analysis plan will be approved and published prior to database lock. The primary analysis of the primary outcome of complete response will be based on the per-protocol set (i.e. all randomised patients receiving the treatment they were randomised to and who provide valid primary outcome data). A sensitivity analysis will be conducted for the intention-to-treat population (i.e. all randomised patients according to their randomised treatment). A generalized linear model with identity link and binomial distribution will be fitted to the primary outcome, with treatment group and centre as independent variables. Non-inferiority of chewing gum to 4 mg ondansetron will be claimed if the lower limit of the two-sided 95% CI for the absolute difference in the proportion of patients achieving complete response for 2 hours after drug administration is greater than -10% for the per-protocol set. If non-inferiority is demonstrated, superiority will be claimed if the same limit is greater than 0% for the intention-to-treat set. Sensitivity analyses will be performed to explore the potential impact of missing data on the results of the primary outcome for the intention-to-treat set. Analysis of the secondary outcomes will follow the intention-to-treat principle and superiority testing will be conducted of chewing gum versus 4 mg ondansetron. A Cox proportional hazards model will be fitted to the time to complete response, with the underlying proportional hazard assumption tested using the scaled Schoenfeld residuals. QoR-15 and SF-12 continuous outcomes will be analysed using linear regression models with baseline value, treatment group and centre as predictors in the model. Count data (number of episodes of nausea, retching and vomiting, and number of rescue treatments) and length-of-stay (duration of PACU stay and duration of hospital stay) will be modelled using generalized linear regression models. Safety outcomes will be summarized according to treatment received. Sub-group analyses will include assessment by age (<18 years and 18 years and older) and by Aboriginal and Torres Strait Islander and Maori status (yes vs no).

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,VIC
Recruitment hospital [1] 10039 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [2] 10040 0
The Royal Childrens Hospital - Parkville
Recruitment hospital [3] 10041 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [4] 10042 0
Princess Margaret Hospital - Subiaco
Recruitment postcode(s) [1] 21559 0
3050 - Parkville
Recruitment postcode(s) [2] 21560 0
3084 - Heidelberg
Recruitment postcode(s) [3] 21561 0
6008 - Subiaco
Recruitment outside Australia
Country [1] 9590 0
New Zealand
State/province [1] 9590 0
Auckland
Country [2] 9591 0
Hong Kong
State/province [2] 9591 0
Hong Kong

Funding & Sponsors
Funding source category [1] 298697 0
Other
Name [1] 298697 0
Australian and New Zealand College of Anaesthetists
Address [1] 298697 0
630 St Kilda Rd., Melbourne VIC 3004
Country [1] 298697 0
Australia
Funding source category [2] 298701 0
Hospital
Name [2] 298701 0
Melbourne Health
Address [2] 298701 0
300 Grattan St, Parkville, VIC, 3050
Country [2] 298701 0
Australia
Primary sponsor type
Hospital
Name
Melbourne Health
Address
300 Grattan St, Parkville, VIC, 3050
Country
Australia
Secondary sponsor category [1] 297871 0
None
Name [1] 297871 0
None
Address [1] 297871 0
Country [1] 297871 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299648 0
Melbourne Health
Ethics committee address [1] 299648 0
300 Grattan St, Parkville, VIC, 3050
Ethics committee country [1] 299648 0
Australia
Date submitted for ethics approval [1] 299648 0
24/01/2018
Approval date [1] 299648 0
19/02/2018
Ethics approval number [1] 299648 0
HREC/18/MH/2

Summary
Brief summary
This trial protocol has been endorsed by the ANZCA Clinical Trials Network.

We aim to conduct a multicentre, randomised controlled trial of the efficacy and safety of peppermint- flavoured chewing gum to treat postoperative nausea and vomiting (PONV) in the post-anaesthesia care unit (PACU). We will test the primary hypothesis that chewing gum is non-inferior to ondansetron in achieving complete cessation of nausea, retching and vomiting within 2 h of administration, with no recurrence between cessation and 2 h after administration, and no rescue medication between administration and 2 h after administration (i.e. complete response) in female patients aged 12 years and older with nausea, retching and/or vomiting in the PACU after volatile anaesthetic-based general anaesthesia for breast or laparoscopic surgery. Chewing gum is a simple and inexpensive drug-free treatment for the common, costly and distressing problem of PONV. This study has the potential to significantly improve clinical and economic outcomes for millions of patients and health services in high-, middle- and low-income nations worldwide.
Trial website
Trial related presentations / publications
Public notes
The data sharing plan for this trial is undecided

Contacts
Principal investigator
Name 81162 0
Dr Jai Darvall
Address 81162 0
Department of Anaesthesia and Pain Management
Royal Melbourne Hospital
300 Grattan St
Parkville, VIC, 3050
Country 81162 0
Australia
Phone 81162 0
+61 3 93427136
Fax 81162 0
Email 81162 0
jai.darvall@mh.org.au
Contact person for public queries
Name 81163 0
Dr Jai Darvall
Address 81163 0
Department of Anaesthesia and Pain Management
Royal Melbourne Hospital
300 Grattan St
Parkville, VIC, 3050
Country 81163 0
Australia
Phone 81163 0
+61 3 93427136
Fax 81163 0
Email 81163 0
jai.darvall@mh.org.au
Contact person for scientific queries
Name 81164 0
Dr Jai Darvall
Address 81164 0
Department of Anaesthesia and Pain Management
Royal Melbourne Hospital
300 Grattan St
Parkville, VIC, 3050
Country 81164 0
Australia
Phone 81164 0
+61 3 93427136
Fax 81164 0
Email 81164 0
jai.darvall@mh.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Undecided
No/undecided IPD sharing reason/comment
Steering committee yet to decide on data sharing
What supporting documents are/will be available?
No other documents available
Summary results
No Results