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Trial registered on ANZCTR


Registration number
ACTRN12618000732280
Ethics application status
Approved
Date submitted
6/04/2018
Date registered
2/05/2018
Date last updated
13/11/2018
Date data sharing statement initially provided
13/11/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Randomised Placebo Controlled Trial of Celecoxib for Acute Burn Inflammation and Fever
Scientific title
Randomised Placebo Controlled Trial of Celecoxib for Acute Burn Inflammation and Fever
Secondary ID [1] 294527 0
Nil known
Universal Trial Number (UTN)
U1111-1212-0324
Trial acronym
CABIN
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute burn injury 307298 0
Condition category
Condition code
Injuries and Accidents 306415 306415 0 0
Burns

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Celecoxib 200mg twice a day as oral capsules for six weeks in addition to standard care.

Adherence to allocated status will be in two phases. In hospital, administration will be recorded by nursing staff. At hospital discharge, participants will be provided with sufficient study medication to day 42. Participants will also be asked to complete a paper record of daily study drug administration. Study drug pill counts will be collected at the 42 day follow up.

Participants will receive routine care at the discretion of the treating team. They will be permitted to have analgesia prescribed as per the departmental analgesia protocol and at discretion of anaesthetists, with the only exception being that participants will be prohibited from receiving any additional NSAID including aspirin.
Intervention code [1] 300827 0
Treatment: Drugs
Comparator / control treatment
Oral capsules with inert filler (microcrystalline cellulose) twice a day for six weeks in addition to standard care
Control group
Placebo

Outcomes
Primary outcome [1] 305426 0
Intention to treat analysis (including all randomised study participants) of scar quality as measured by participant reported Patient Observer Scar Assessment Scale
Timepoint [1] 305426 0
day 42 post-enrolment
Secondary outcome [1] 345191 0
Hospital cost of care - assessed using individual participant hospital accounting data
Timepoint [1] 345191 0
day 42 post-enrolment
Secondary outcome [2] 345192 0
Quality of Recovery - 15 (QoR-15) score at post-op day 1 in surgically managed participants
Timepoint [2] 345192 0
post-op day 1
Secondary outcome [3] 345193 0
Severity of pain and impact on function as per Brief Pain Inventory (short form)
Timepoint [3] 345193 0
day 14 post-enrolment and day 42 post-enrolment
Secondary outcome [4] 345195 0
Total number of inpatient days - Blinded assessment of medical records.
Timepoint [4] 345195 0
day 42 post-enrolment
Secondary outcome [5] 345196 0
Post-operative inpatient days - Blinded assessment of medical records.
Timepoint [5] 345196 0
day 42 post-enrolment
Secondary outcome [6] 345197 0
Incident sepsis (SEP-3 criteria) - blinded assessment of medical records.
Timepoint [6] 345197 0
day 42 post-enrolment
Secondary outcome [7] 345198 0
Incident infection - blinded assessment of medical records.
Timepoint [7] 345198 0
day 42 post-enrolment
Secondary outcome [8] 345199 0
Number of participants with >95% wound healing - by blinded clinician
Timepoint [8] 345199 0
day 14 post-enrolment and day 42 post-enrolment
Secondary outcome [9] 345201 0
Number of participants requiring repeat surgery for graft loss - blinded assessment of medical records.
Timepoint [9] 345201 0
day 42 post-enrolment
Secondary outcome [10] 345202 0
Quality of life by Short Form- 36 (SF-36)
Timepoint [10] 345202 0
day 42 post-enrolment
Secondary outcome [11] 345203 0
Functional recovery (quick dash or lower limb functional index)
Timepoint [11] 345203 0
day 42 post-enrolment and 3 months post-enrolment
Secondary outcome [12] 345205 0
Modified Vancouver Scar Scale components (pigment, pliability, vascularity, height) - by blinded clinician
Timepoint [12] 345205 0
day 42 post-enrolment and 3 months post-enrolment
Secondary outcome [13] 346179 0
Incidence of septic shock (SEP-3 criteria) - blinded assessment of medical records
Timepoint [13] 346179 0
day 42 post-enrolment
Secondary outcome [14] 346180 0
Number of inpatient days with temperature >38 oC - blinded assessment of observation charts
Timepoint [14] 346180 0
hospital discharge, censored at day 14 post-enrolment
Secondary outcome [15] 346186 0
Per-protocol analysis (including only participants with >80% recorded adherence to study medication) of scar quality as measured by participant reported Patient Observer Scar Assessment Scale
Timepoint [15] 346186 0
day 42 post-enrolment

Eligibility
Key inclusion criteria
Less than 48 hours from admission to the burns unit with acute burn injury
OR
Outpatient booked for day of surgery admission for management of acute burn injury
Minimum age
18 Years
Maximum age
65 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
i. Regular NSAID use prior to injury (including any dose aspirin)
ii. Major burn with TBSA>20% or requiring admission to the intensive care unit
iii. Enrolment not considered in the patient’s best interest
iv. Previously enrolled in the CABIN Fever study
v. Participating in a competing interventional study
vi. Pregnancy or breast feeding
vii. NSAID or sulphonamide allergy
viii. Renal dysfunction (eGFR <60)
ix. Angina, myocardial infarction, heart failure (NYHA class II or greater: ordinary physical activity results in fatigue, palpitations or dyspnoea)
x. Previous history of peripheral arterial disease or stroke
xi. Current use of angiotensin converting enzyme inhibitor or angiotensin II receptor blocker
xii. Suspected or confirmed hepatic cirrhosis, portal hypertension or variceal bleeding
xiii. Current ALT 3x upper limit of normal or Bilirubin 2x upper limit of normal
xiv. Previous history of gastric ulcer or gastrointestinal bleeding
xv. Current systemic corticosteroid use
xvi. Suspected or confirmed haemophilia
xvii. Current use of anticoagulant medications including warfarin, new oral anticoagulants (NOACs) such as apixaban, dabigatran and rivaroxaban and treatment dose heparin
xviii. Suspected or confirmed thrombophilia or previous history of thromboembolism

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 sequence will be concealed from investigators, study staff and participants. The Fiona Stanley Hospital clinical trials pharmacist will generate the randomisation sequence. This sequence will be used to supply sequentially numbered bottles of blinded study medication to the ward based investigators.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A permuted block randomisation method will be used with random variable block sizes with no stratification. The sequence will be generated using online software (sealedenvelope.com, Sealed Envelope Ltd., UK).
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
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint(s)
Efficacy
Statistical methods / analysis
In an interventional study of acute burns <50% total body surface area (TBSA), mean Patient Observer Scar Assessment Scale (POSAS) observer scores in the control group were 4.56/10 with a standard deviation of 1.54 (Gardien, Marck et al. 2016). A clinically significant improvement was attributed to the intervention with a fall of 18% in mean POSAS. A similar distribution was documented in a population of patients with TBSA <20%, mean POSAS was 3.42/10, with a standard deviation of 1.31 (Goei, van der Vlies et al. 2016). Assuming a baseline of 3.42 and SD of 1.31 and P=0.05, a study with 113 participants randomised in a 1:1 ratio has 80% power to detect a clinically significant 20% reduction in POSAS. With a 20% adjustment for non-normal distribution and 10% loss to follow-up, the final target is 150 participants. There were 350 patients admitted in the 2016 calendar year, of these 282 were within the target age group (18-65) and TBSA (<20%). We would therefore need to recruit 35% of eligible patients over an 18-month period to reach our target.

The primary analysis population is the intention to treat population defined as all study participants. There will be no imputation for missing data. A second per protocol analysis will be conducted including participants with adherence to study medication of >80%.

Normally and non-normally distributed data will be presented as mean and standard deviation, and median and interquartile range, respectively. Between-group comparison of parametric data will be provided as mean difference and confidence interval and analysed using Student’s t test. Between-group comparison of non-parametric data will be presented as median difference and analysed using the Wilcoxon-Mann-Whitney U test. For dichotomous data, frequencies and percentages will be presented and between-group analysis will use Fischer’s Exact or Chi-squared test as appropriate.

Secondary analysis will also be conducted adjusting the primary outcome variable for prespecified baseline covariates (age, gender, TBSA, depth of injury, infection at presentation, delayed presentation) in a transformed multivariable linear regression model including baseline univariate variables with a p<0.25. For all outcome analyses a two-sided p value of <0.05 will be considered significant. Subgroup analyses will be performed on the pre-specified subgroups of interest irrespective of whether there is evidence of a treatment effect. Heterogeneity between subgroups will be determined by fitting an interaction between treatment and subgroup.

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
Recruitment hospital [1] 10587 0
Fiona Stanley Hospital - Murdoch
Recruitment postcode(s) [1] 22304 0
6150 - Murdoch

Funding & Sponsors
Funding source category [1] 299154 0
Government body
Name [1] 299154 0
WA Health
Address [1] 299154 0
Level 2, Block C
189 Royal Street
EAST PERTH WA 6004
Country [1] 299154 0
Australia
Funding source category [2] 299156 0
Charities/Societies/Foundations
Name [2] 299156 0
Fiona Wood Foundation
Address [2] 299156 0
Fiona Stanley Hospital
CD15, Level 4, Burns Unit
11 Robin Warren Dve
Murdoch WA 6150
Country [2] 299156 0
Australia
Funding source category [3] 299157 0
Charities/Societies/Foundations
Name [3] 299157 0
Spinnaker Health Research Foundation
Address [3] 299157 0
Fremantle Hospital
Room 27B, G Block
Alma Street
Fremantle WA 6160
Country [3] 299157 0
Australia
Primary sponsor type
Hospital
Name
Fiona Stanley Hospital
Address
11 Robin Warren Dve
Murdoch WA 6150
Country
Australia
Secondary sponsor category [1] 298410 0
None
Name [1] 298410 0
Address [1] 298410 0
Country [1] 298410 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300079 0
South Metropolitan Health Service Health Research Ethics Committee
Ethics committee address [1] 300079 0
Level 2, Education Building, Fiona Stanley Hospital
14 Barry Marshall Parade
MURDOCH Western Australia 6150
Ethics committee country [1] 300079 0
Australia
Date submitted for ethics approval [1] 300079 0
29/12/2017
Approval date [1] 300079 0
07/03/2018
Ethics approval number [1] 300079 0
RGS731

Summary
Brief summary
Background
The tissue trauma of burn injury incites a unique cascade of inflammatory cytokines that leads to acute local and systemic complications. Chronic inflammation contributes to increased morbidity and mortality that persists for more than 20 years after injury. Scar quality is a global indicator of acute recovery and predictor of long term complications. Despite receiving optimal surgical management, almost half of injuries result in hypertrophic scarring. Adjunctive therapies to complement contemporary surgical burns management are urgently needed and non-steroidal anti-inflammatory drugs (NSAIDs) are prime candidates. Despite extensive and promising pre-clinical data, there have been no clinical trials.

Aims
By conducting a randomised controlled trial, we aim to answer the important, original research questions:
(1) Does early and sustained use of the non-steroidal anti-inflammatory drug, celecoxib, following acute burn injury improve recovery as measured by scar quality at six weeks?
(2) Does the use of celecoxib attenuate the persistent aberrant inflammatory response?

Significance
Scar quality is an important, patient centred outcome that reflects every intervention from the time of injury and is associated with long term quality of life. Annual costs of burn injury to WA Health are $11m with individual costs correlated with time to healing. Improving quality of recovery will facilitate return of physical and psychological wellness for the patients and reduce their need for ongoing healthcare.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 82502 0
Dr Edward Raby
Address 82502 0
State Adult Burns Unit
Fiona Stanley Hospital
11 Robin Warren Drive
Murdoch Western Australia 6150
Country 82502 0
Australia
Phone 82502 0
+61 8 6152 2222
Fax 82502 0
Email 82502 0
edward.raby@health.wa.gov.au
Contact person for public queries
Name 82503 0
Dr Edward Raby
Address 82503 0
State Adult Burns Unit
Fiona Stanley Hospital
11 Robin Warren Drive
Murdoch Western Australia 6150
Country 82503 0
Australia
Phone 82503 0
+61 8 6152 2222
Fax 82503 0
Email 82503 0
edward.raby@health.wa.gov.au
Contact person for scientific queries
Name 82504 0
Dr Edward Raby
Address 82504 0
State Adult Burns Unit
Fiona Stanley Hospital
11 Robin Warren Drive
Murdoch Western Australia 6150
Country 82504 0
Australia
Phone 82504 0
+61 8 6152 2222
Fax 82504 0
Email 82504 0
edward.raby@health.wa.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Undecided
No/undecided IPD sharing reason/comment
Awaiting Human Research and Ethics Committee review specific to data sharing
What supporting documents are/will be available?
Study protocol
Summary results
No Results