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Trial registered on ANZCTR


Registration number
ACTRN12620000396921
Ethics application status
Approved
Date submitted
26/02/2020
Date registered
23/03/2020
Date last updated
23/03/2020
Date data sharing statement initially provided
23/03/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Does gabapentin decrease the incidence of postoperative pain in children undergoing tonsillectomy procedures?
Scientific title
A multi-centre, double-blinded randomised placebo-controlled study to investigate Gabapentin use to manage post tonsillectomy pain
Secondary ID [1] 300640 0
Nil known
Universal Trial Number (UTN)
NIL
Trial acronym
GAP
Linked study record
NIL

Health condition
Health condition(s) or problem(s) studied:
Pain following tonsillectomy surgery 316418 0
Condition category
Condition code
Anaesthesiology 314674 314674 0 0
Pain management
Oral and Gastrointestinal 314675 314675 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study will be a randomized, double-blinded and placebo-controlled study.
Following approval from the treating anaesthetist and voluntary written informed consent by the parent/guardian, the recruited children will be block randomised and assigned to one of the two groups, in a 1:1 ratio to receive either gabapentin (100mg/ml) suspension or placebo suspension.
The blinding of the drug will be performed by the Clinical Trials Pharmacy who will provide us with the un-blinding folders/envelopes for the study. Participants, research assistants, nurses and doctors will be blinded to the allocation. We will call the study suspensions by the word syrup in our information sheets to the families in order to ensure readability and understanding of the study information.

Participants will receive 0.06 ml/kg of their assigned suspension (rounded to the nearest 0.1 ml) for their first preoperative dose, approximately 45 minutes before induction. Subsequently, they will receive 0.03 ml/kg of their assigned suspension (rounded to the nearest 0.1 ml) three times a day by mouth on days 0, 1, & 2, which equates to 3 mg/kg dose gabapentin or placebo. They will receive at least 2 doses on Day 0 (DO) during their in-patient hospital stay and this will include the first preoperative dose. The dose will be titrated up to 0.06 ml/kg (6 mg/kg gabapentin if in the active group) three times daily from the morning of day 3, for days 3, 4 & 5. On day 6 & 7 the dose will reduce to previous 0.03 ml/kg three times daily before stopping on day 8. Participants will receive medication for 8 days (D0-D7).

The study medications are in addition to the standard medications normally prescribed post tonsillectomy.

There will be active follow up with the families to ensure study adherence. All families are provided with a standard diary to document medication administration following tonsillectomy surgery. Our families will also be provided with a study diary where they will document further information. They will also report this in the study database via survey links sent daily.
Intervention code [1] 316969 0
Treatment: Other
Comparator / control treatment
Placebo controlled.
Placebo composition will be Visco PLUS SV and Visco Sweet SFB.

Both the gabapentin and placebo will be sourced and prepared by Perth Children’s Hospital clinical trials pharmacy and will look and taste similar.
Control group
Placebo

Outcomes
Primary outcome [1] 323001 0
The primary outcome measure will be self-reported pain intensity using the Faces Pain Scale -revised (FPS-R) assessed 4 times daily for 7 days. Patients will be asked to rate pain intensity twice in the morning and twice in the evening. At each time point they will be asked first to rate pain just before the meal (pain at rest) and then rate again with eating (pain on swallowing).
Timepoint [1] 323001 0
Pain scores will be assessed 4 times a day for 7 days.
The pain intensity score for each of the 4 daily time points will be compared between groups over time i.e. morning at rest gabapentin vs placebo, morning with swallowing gabapentin vs placebo, evening at rest gabapentin vs placebo, evening with swallowing gabapentin vs placebo. Pain intensity scores will be collected across the days and compared between the 2 groups.
Secondary outcome [1] 380496 0
Comparison of ‘as required’ opioids (number of doses and total oral Morphine equivalents) following surgery by each group.
Families will be provided with diaries to document medication use following surgery. This information will be fed into the study database via survey links sent to to them.
Timepoint [1] 380496 0
Each day post tonsillectomy for a minimum of 14 days or until the child is pain free without analgesia and has returned to normal activities
Secondary outcome [2] 380497 0
Comparison of observed daily pain score as measured by (a) the Post-Operative Parental Pain Measure (PPPM) and (b) parent reported pain score (Verbal Rating Scale -VRS- 0-10) between the gabapentin group and placebo groups each day.
Timepoint [2] 380497 0
Each day post tonsillectomy for a minimum of 14 days or until the child is pain free without analgesia and has returned to normal activities
Secondary outcome [3] 380498 0
Comparison of unplanned medical representations for (a) pain and (b) any reason following surgery.
Families will be provided with study diaries where they can document any representations. This information will be fed into the study database via survey links sent to to them.
Timepoint [3] 380498 0
Post tonsillectomy for a minimum of 14 days or until the child is pain free without analgesia and has returned to normal activities
Secondary outcome [4] 380499 0
Acceptability of gabapentin suspension to parents, by comparing Global Satisfaction Score (NRS 0-10), compliance with dosing (% completing >90% of doses) and reported side-effects and withdrawals between groups
Timepoint [4] 380499 0
Post tonsillectomy followup is for a minimum of 14 days or until the child is pain free without analgesia and has returned to normal activities
Secondary outcome [5] 380500 0
Composite Outcome: Acceptability of suspension [Parent and Child] pre-operatively and repeated at end of treatment.

It will be measured using a 5-point Likert scale (1 = completely unacceptable; 5 = completely acceptable)
Timepoint [5] 380500 0
pre-operatively and repeated at end of treatment
Secondary outcome [6] 380501 0
Safety of Oxycodone and gabapentin together by review of the occurrence of sedation events (if any), such as feeling drowsy, dizziness, lack of coordination, feeling tired, in hospital pulse oximetry data, reported adverse events and any medical representations.

This information will be gathered from the medical notes and from review of the participant.
Timepoint [6] 380501 0
In hospital post tonsillectomy

Eligibility
Key inclusion criteria
Children aged 4-16 years
Undergoing elective surgery under general anaesthetic for tonsillectomy +/- adenoidectomy +/- grommets or cautery inferior turbinates
Staying overnight in hospital
Minimum age
4 Years
Maximum age
16 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Severe obstructive sleep apnoea documented on a sleep study
• Cardiovascular, respiratory or neurological disease giving an ASA III or above status
• Known renal impairment
• Regular preoperative use of anticonvulsants, analgesics or any concomitant use of central nervous system depressants
• Known hypersensitivity to the active substance or to any of the excipients listed
• Patients will be excluded if language barriers impede data collection or if the Department for Child Protection and Family Support is involved in their care
• Patients will be excluded if they have planned admissions to the Paediatric Intensive Care Unit (PICU)
• Current or previous mental health concerns

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)
Allocation concealment by numbered containers of gabapentin/placebo syrup.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computer-generated block randomisation will be used.
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
Multi-centre trial
Phase
Phase 4
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
The data will be analysed as a longitudinal model. The analysis will indicate any differences in the two treatments (gabapentin or placebo) and the change in pain score over time (days). More specifically, the model will include the effect of treatment, and measurement condition (at rest or swallowing), both over time, a random intercept for subject (to account for different baseline pain scores), a subject-specific random slope for treatment, and other study measurements detailed above (such as demographic variables Age, ASA, etc.).

Note that the longitudinal nature of the model will allow missing responses at a few time points. If substantial pain measurement data is missing then a decision will be made either to omit the record from analysis, or to impute the data using a standard technique (such as multiple imputation based on chained equations).
Regarding secondary outcomes, these will be assessed as follows.
Daily Pain intensity scores as reported by parents (PPPM and NRS scales) will be analysed using the same repeated measures model, as for the children’s pain scores.
The amount of opioid administered to each group over the days will be analysed as a repeated measures model.
The number of unplanned medical presentations, episodes of vomiting, for each group will be analysed as a Poisson log-linear model or a contingency table using a chi square test of association.
Other variables like side effects, UMSS, PAEDS, adverse events, compliance with medication, need for oxygen therapy following PACU for each group will be analysed using a contingency table using a chi square test of association.
The global satisfaction for treatment by parents will be analysed as a contingency table using a chi square test of association, or as a binomial log-linear model.
Demographics (age, weight, ASA, length of stay and operation data) will be included in the statistical modelling. Summary statistics will also be presented to enable and simplify direct group comparisons.

Sample size estimation Given the complexity of the data, simulations were conducted to help with sample size calculations. The data for the treatment groups were simulated based on mean difference of 1 in pain scores deemed clinically significant. It was also expected that for all treatment groups the average pain scores will decrease over time. Based on 500 simulations, the power is calculated as the proportion of times the null hypothesis is rejected, based on a repeated measures model for the pain scores. The mean pain vectors were taken as muTreat = (10, 8, 6, 4, 2, 1, 1) and muPlacebo =(10, 9, 8, 6, 5, 3, 3), with a constant (over time) standard deviation of 3. The simulations were repeated with several different parameter values (in particular a range of values for the mean vector around the mean specified above), and a sample size of 85 per group was deemed to be reasonable. Simulations gave a power of 0.9 for a sample size of 85 per group. The power for a corresponding two-sample t-test with 85 patients and same standard deviation is only 70%. 15 patients are added per group to allow for loss in follow-up, cancellation of surgery, change of surgical plan and other protocol violations.
Interim analyses will be carried out after 20 and 50 patients respectively and the blinded data reviewed by an independent Drug Safety Monitoring Committee (DSMC). It will be un-blinded at their request. The initial 50 patients will be recruited only from Perth Children’s’ Hospital and morning lists only.
The first interim analysis for safety and adverse events will occur after 10 patients for each group. We will compare groups for excessive sedation post operatively, airway interventions or review requirements between groups, number of children with altered oxycodone prescriptions, comparison of reports of adverse events or medical representations between groups from the Day 2-4 phone reviews.
An interim analysis of futility will be performed after 50 recruited patients, 25 in each group, we will maintain the blinding and analyse the groups with regard to compliance, side effects, efficacy and representations. Review by data monitoring committee will be requested and un-blinding if necessary under the following conditions:
If 6 (25%) or more children in a group refuse to take suspension,
If 6 (25%) or more children from a group withdraw due to side effects of the study medication (sedation, nausea, vomiting or dizziness)
If unplanned medical representations (any cause) exceeds 13 in any group (>50% previously seen)
If > 8 (30%) are lost to follow-up or withdraw from the study in the follow up period
We will also assess the daily PPPM between groups to assess efficacy.

Recruitment
Recruitment status
Not yet 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] 15980 0
Perth Children's Hospital - Nedlands
Recruitment postcode(s) [1] 29470 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 305064 0
Hospital
Name [1] 305064 0
Perth Children's Hospital
Address [1] 305064 0
Department of Anaesthesia and Pain Medicine
Perth Children's Hospital
15 Hospital Avenue
Nedlands
WA 6009
Country [1] 305064 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
Telethon Kids Institute
Address
Northern Entrance
Perth Children's Hospital
15 Hospital Avenue
Nedlands
WA 6009
Country
Australia
Secondary sponsor category [1] 305429 0
None
Name [1] 305429 0
Address [1] 305429 0
Country [1] 305429 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305450 0
Child and Adolescent Health Services Ethics Committee
Ethics committee address [1] 305450 0
Level 5
Perth Children's Hospital
15 Hospital Avenue
Nedlands
WA 6009
Ethics committee country [1] 305450 0
Australia
Date submitted for ethics approval [1] 305450 0
21/05/2019
Approval date [1] 305450 0
15/10/2019
Ethics approval number [1] 305450 0
RGS0000003273

Summary
Brief summary
Pain following tonsillectomy is a big problem for many children. At Perth Children’s Hospital as at other centres, there is a high rate of unplanned re-presentation to hospital with many of these visits due to pain. Some of the pain experienced by children after having their tonsils out is likely neuropathic in nature and less responsive to the standard pain killers which are currently prescribed. There are concerns about the use of the currently used pain relieving medicines for example regular anti-inflammatories in the setting of poor oral intake post operatively and worries over their effects on bleeding risk or the use of opioids in this population at risk of breathing difficulty. Studies to date using gabapentin (a well-known drug to treat neuropathic pain) preoperatively have been encouraging showing a reduction in early pain, strong pain killer requirement and of their side effects. There have been no studies in children using an extended course of the medicine.

To help improve post-operative pain management we aim to assess the impact of perioperative gabapentin on postoperative pain levels through a placebo-controlled trial. We will also monitor the return to normal of a number of functional outcomes, for example, eating pattern, sleeping pattern, vomiting. If gabapentin is shown to be effective, then children will not only benefit from reduced pain but may also require less additional doses of breakthrough strong pain killers. Furthermore, better pain control will reduce the number of re-presentations to their general practitioners or hospital benefiting the Health System as a whole.

We hypothesise that (1) Gabapentin will significantly decrease the postoperative child and parental reported pain scores following tonsillectomy. 2) Gabapentin will reduce the breakthrough opioid requirement in children following a tonsillectomy. 3) Gabapentin will reduce the medical re-attendance rate for pain following adenotonsillectomy.
Trial website
None
Trial related presentations / publications
None
Public notes

Contacts
Principal investigator
Name 100430 0
Prof Britta Regli-von Ungern-Sternberg
Address 100430 0
Perth Children's Hospital
15 Hospital Avenue
Nedlands
WA 6009
Country 100430 0
Australia
Phone 100430 0
+61420790101
Fax 100430 0
Email 100430 0
Britta.Regli-VonUngern@health.wa.gov.au
Contact person for public queries
Name 100431 0
Prof Britta Regli-von Ungern-Sternberg
Address 100431 0
Perth Children's Hospital
15 Hospital Avenue
Nedlands
WA 6009
Country 100431 0
Australia
Phone 100431 0
+61420790101
Fax 100431 0
Email 100431 0
Britta.Regli-VonUngern@health.wa.gov.au
Contact person for scientific queries
Name 100432 0
Prof Britta Regli-von Ungern-Sternberg
Address 100432 0
Perth Children's Hospital
15 Hospital Avenue
Nedlands
WA 6009
Country 100432 0
Australia
Phone 100432 0
+61420790101
Fax 100432 0
Email 100432 0
Britta.Regli-VonUngern@health.wa.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Investigators for the study are still deciding upon how to proceed with this.
What supporting documents are/will be available?
No other documents available
Summary results
No Results