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Trial registered on ANZCTR


Registration number
ACTRN12615000041550
Ethics application status
Approved
Date submitted
22/12/2014
Date registered
20/01/2015
Date last updated
26/07/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
Celecoxib affecting inflammation following thoracic and abdominal surgery (Phase II study)
Scientific title
Celecoxib's effect on inflammatory response in patients receiving thoracic and abdominal surgery (Phase II study)
Secondary ID [1] 285885 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Inflammatory response to surgery.
While the trial is being conducted at a cancer hospital, not all patients in this trial will be receiving cancer resection surgery. For instance, patients who have had colonic cancer resected and are receiving a follow-up procedure for repair of epigastric hernia, would be eligible.
293804 0
Condition category
Condition code
Anaesthesiology 294109 294109 0 0
Anaesthetics
Surgery 294187 294187 0 0
Other surgery

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients are randomised to receive oral Celecoxib through the perioperative period, or no anti-inflammatory prescription.
Specifically, patients in the Celecoxib group receive a loading dose of 400mg of oral Celecoxib capsules within 30 minutes prior to the induction of anaesthesia for surgery. Subsequently they receive 200mg of oral Celecoxib capsules at 12hourly intervals for a total of six dosing episodes (3 days).

A ‘half-dose’ regimen will be adopted (200mg loading dose followed by 100mg every 12 hours for a total of six dosing events) in the following scenarios at registration:
* Multiple cardiovascular risk factors: (any two of the following)
1. History of atherosclerotic disease;
2. Hypertension (treated with Angiotensin Converting Enzyme inhibitors, Angiotensin II receptor antagonists);
3. Cardiac failure (NYHA I).
* Age older than 65 years as well as body weight less than 50kg.
* Pre-operative Serum Creatinine of 100–149umol/L.

Monitoring:
Patients are seen daily on the wards by both treating clinicians and the study researchers following their surgery. Specifically, adverse events are enquired about, pain scores documented and standard post-operative blood tests acquired to monitor renal function. Pill compliance is documented. Patients are deemed compliant if they take at least 5/6 requested drug episodes.

Additional to the standard post-operative bloods are post-operative blood tests that are taken at baseline (induction), and then 6hrs, 24hrs and 48hrs hours following surgery. These tests are for research purposes to measure the effectiveness of Celecoxib in limiting the prostaglandin rise (inflammatory response to surgery). A baseline urine sample and 48 hour urine same is also collected.
Intervention code [1] 290866 0
Treatment: Drugs
Comparator / control treatment
No anti-inflammatory treatment. There is no placebo in this trial. Patients in the non-Celelcoxib group will not be receiving an anti-inflammatory and are not blinded to the intervention.
Control group
Active

Outcomes
Primary outcome [1] 293905 0
Plasma prostaglandin E metabolite at 48 hours following surgery commencement as measured by immunoassay.
Timepoint [1] 293905 0
48-hour plasma prostaglandin E metabolite compared with baseline.
Primary outcome [2] 299055 0
Urine prostaglandin E metabolite at 48 hours following surgery commencement as measured by immunoassay.
Timepoint [2] 299055 0
48-hour urine prostaglandin E metabolite compared with baseline.
Secondary outcome [1] 312128 0
Acute pain (rest and coughing) scores in patients receiving thoracic or laparotomy (major abdominal) surgery
Timepoint [1] 312128 0
6hr, 24hr, 36hr and 48hr post surgery 1-10 Visual analogue (resting and movement) scores
Secondary outcome [2] 312268 0
Incidence of renal injury as evident by Serum Creatinine level greater than 0.15 mmol/L.
Timepoint [2] 312268 0
Serum Creatinine level greater than 0.15 mmol/L at 48 hours post surgery
Secondary outcome [3] 324800 0
Perioperative inflammatory cytokine (IL-1beta, IL-6, IL-10) changes in response to surgery. Cytokines will be assessed using flow cytometry (multiplexed bead-based immunoassay) from the plasma sample provided by study participants..
Timepoint [3] 324800 0
6hr, 24hr and 48hr post surgery cytokine levels (IL-1beta, IL-6, IL-10).

Eligibility
Key inclusion criteria
- Patients receiving thoracic surgery or laparotomy (expected duration greater than two hours) at Peter MacCallum Cancer Centre. Surgical subtypes include patients receiving thoracotomy or thoracoscopic surgery where surgery is performed in the intra-pleural space, and patients receiving a laparotomy (expected >2 hours);
- Age >18 years old;
- World Health Organization ECOG performance status 0 or 1;
- At least five days since use of prior non-steroidal anti-inflammatory agents including Aspirin, Celecoxib, Ibuprofen, Naproxen, Meloxicam, Diclofenac;
- Written, informed consent.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
contraindications to celecoxib,
robotic assisted thoracoscopic surgery,
acute inflammatory condition (sepsis, infection),
pregnancy or lactation,
concurrent use of oral corticosteroid treatment or NSAID/aspirin (within a week prior to study entry),
presence of neuroendocrine tumour,
hepatic impairment (aspartate transaminase >240 u/L, alanine transaminase >110 u/L) renal impairment (creatinine >150 umol/L).

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)
Recruitment of patients for the study will usually occur at the Peter MacCallum Cancer Centre’s Pre-Anaesthesia Clinic (PAC). Typically, patients are seen in the PAC for an hour by an anaesthetist and anaesthetic nurse up to four weeks prior to surgery; four weeks will be an allowable time window prior to surgery. Patients have an electrocardiograph (ECG) performed and are asked to provide blood samples for routine preoperative testing. Following consultation, patients will be approached regarding participation in the study by an investigator who is independent of the patient’s treatment. This occasion will be used for the research nurse to discuss with the potential participant the aspects of participation in the study. The patient will be given the opportunity to ask questions and will be provided with a Participant Information and Consent Form. Informed consent will be achieved prior to signed and witnessed written consent. Patients who have consented for participation will be registered and given a de-identified study number.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Allocation to the Celecoxib or control arms will occur on the day of surgery using the closed envelope method, where patients are randomised using serially numbered envelopes. The random allocation sequence will be computer generated using random block sizes by the study biostatistician who will then independently prepare the envelopes prior to the commencement of accrual. Envelopes will be securely stored by the study coordinator who would be contacted by the treating clinician to request access to a new patient’s treatment arm (on the day of surgery). The secrecy of the contents of the closed envelopes will be maintained using double envelopes.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Analyses for the study will be per protocol based on compliance with 5/6 dosing events and meeting all of the inclusion and exclusion criteria. Baseline patient characteristics will be summarised for the whole sample and by treatment arm using descriptive statistics and will be reported for continuous variables as number of patients, mean, median, standard deviation, minimum and maximum; and for categorical variables as counts and percentages.

It is intended to report endpoints for all patients together, regardless of surgery type. It is hoped that there will be similar numbers of patients with each surgery type randomised to each arm, thus the randomised comparisons between arms of the endpoints will not be compromised by the addition of another type of surgery to the population of study.

For each of the primary endpoints the mean difference between the treatment arms will be calculated. Hypothesis testing will be performed for each endpoint at each time point separately using the appropriate statistical test based on the distribution of data. An independent two-sample t-test will be used if data are normally distributed or if an appropriate transformation can be found, otherwise a non-parametric Mann-Whitney U test will be performed. Given the exploratory nature of this pilot study, no adjustments for multiple comparisons will be made.

Pain scores at rest and movement will be summarised descriptively by treatment arm and mean differences between the treatment arms will be estimated.

To assess the safety of the Celecoxib dosing regimen, the incidence of post-operative adverse events, in particular, raised post-operative creatinine will be calculated separately for each treatment arm.


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] 3295 0
Peter MacCallum Cancer Institute - East Melbourne
Recruitment postcode(s) [1] 9079 0
8001 - Melbourne

Funding & Sponsors
Funding source category [1] 290468 0
Self funded/Unfunded
Name [1] 290468 0
Address [1] 290468 0
Country [1] 290468 0
Primary sponsor type
Hospital
Name
Peter MacCallum Cancer Centre
Address
St Andrews Place
East Melbourne
Victoria 8001.
Country
Australia
Secondary sponsor category [1] 289170 0
None
Name [1] 289170 0
Address [1] 289170 0
Country [1] 289170 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292137 0
Peter MacCallum Ethics Committee
Ethics committee address [1] 292137 0
Level 4, 10 St Andrews Place
East Melbourne, 3002
Victoria
Ethics committee country [1] 292137 0
Australia
Date submitted for ethics approval [1] 292137 0
Approval date [1] 292137 0
09/01/2015
Ethics approval number [1] 292137 0
13/06

Summary
Brief summary
This is a 30 patient single-centre, open-labeled, randomised pilot study assessing the effectiveness of a cyclooxygenase (Cox)-II specific inhibitor, Celecoxib, in reducing perioperative inflammation associated with thoracic and major abdominal surgery as assessed by blood and urinary markers. Information regarding Celecoxib's capacity to reduce perioperative pain and morphine consumption will also be sought. Patients will receive standard dosing of Celecoxib in accordance with on-license use. Demonstration of effect and feasibility of inflammation suppression is intended to lead to a multi-centre study investigating the use of perioperative Celecoxib to delay cancer recurrence following Non-Small Cell Lung Cancer (NSCLC) resection surgery.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 53690 0
Dr Jonathan Hiller
Address 53690 0
Peter MacCallum Cancer Centre
St Andrews Place
East Melbourne,
Victoria, 8001
Country 53690 0
Australia
Phone 53690 0
+61 3 96561111
Fax 53690 0
Email 53690 0
jonathan.hiller@petermac.org
Contact person for public queries
Name 53691 0
Dr Jonathan Hiller
Address 53691 0
Peter MacCallum Cancer Centre
St Andrews Place
East Melbourne,
Victoria, 8001
Country 53691 0
Australia
Phone 53691 0
+61 3 96561111
Fax 53691 0
Email 53691 0
jonathan.hiller@petermac.org
Contact person for scientific queries
Name 53692 0
Dr Jonathan Hiller
Address 53692 0
Peter MacCallum Cancer Centre
St Andrews Place
East Melbourne,
Victoria, 8001
Country 53692 0
Australia
Phone 53692 0
+61 3 96561111
Fax 53692 0
Email 53692 0
jonathan.hiller@petermac.org

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary