Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622001527752
Ethics application status
Approved
Date submitted
30/11/2022
Date registered
12/12/2022
Date last updated
1/06/2023
Date data sharing statement initially provided
12/12/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Optimising care following major surgery to prevent clots: How much intervention is really needed and at what cost?
Scientific title
Should intermittent pneumatic compression devices be standard therapy for the prevention of venous thrombo-embolic events: a randomised clinical trial in patients undergoing surgery
Secondary ID [1] 308368 0
Nil Known
Universal Trial Number (UTN)
Trial acronym
IMPOSTERS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Venous thromboembolism 328159 0
Pulmonary Embolism 328160 0
Deep vein thrombosis 328161 0
Diseases of the vasculature and circulation including the
lymphatic system 328407 0
Clotting disorders 328408 0
Condition category
Condition code
Surgery 325214 325214 0 0
Other surgery

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Group A: Participants are treated with low molecular weight heparin (LMWH) plus graduated compression stockings (GCS) for a standard procedural timeframe (see below) plus intermittent pneumatic compression devices (IPCDs) for 5 days.
Timing
Graduated compression stockings are applied by a nurse prior to surgery.
IPCDs are applied by the anaesthetic nurse in the theatre prior to surgery.
The anaesthetist gives the dose of clexane during or after surgery depending on the treating team.
Dose/Duration
The dose of LMWH administration will be determined, in accordance with local hospital guidelines. This is 40mg given at night by the ward nurse and ordered by the treating team. The dose may vary due to the weight of the patient as per guidelines. The duration is dependent on the treating team. Some will be up until discharge from the hospital and some will have extended clexane prophylaxis.
GCS and IPCDs are to be worn continuously every day unless bathing. For the IPCDs that are to be removed when walking.
The duration of GCS is the hospital length of stay and then for 28 days. The IPCDs are to be worn up to and at day 5, unless discharged home.

Strategies
The administration of Clexane can be monitored through paper or digital medication charts. The research nurse at each site is responsible for checking patients twice daily for compliance. The patient is also given a simple diary that allows them to document how long they were removed.
The research nurse will be responsible for checking the correct size of the GCS and the IPCDs.
Intervention code [1] 324816 0
Prevention
Intervention code [2] 324817 0
Treatment: Devices
Comparator / control treatment
Group B: Participants are treated with low molecular weight heparin (LMWH) as per standard clinical recommendations (dosing regimen depending on participant characteristics). These patients are also given below graduated compression stockings (GCS) to wear.
Timing
Graduated compression stockings are applied by a nurse prior to surgery.
The anaesthetist gives the dose of clexane during or after surgery depending on the treating team.
Dose/Duration
The dose of LMWH administration will be determined, in accordance with local hospital guidelines. This is 40mg given at night by the ward nurse and ordered by the treating team. The dose may vary due to the weight of the patient as per guidelines. The duration is dependent on the treating team. Some will be up until discharge from the hospital and some will have extended clexane prophylaxis.
GCS are to be worn continuously every day unless bathing. The duration of GCS is the hospital length of stay and then for 28 days.

Strategies
The administration of Clexane can be monitored through paper or digital medication charts. The research nurse at each site is responsible for checking patients twice daily for compliance. The patient is also given a simple diary that allows them to document how long they were removed.
The research nurse will be responsible for checking the correct size of the GCS.
Control group
Active

Outcomes
Primary outcome [1] 333053 0
•Symptomatic Venous thromboembolism. This is either deep vein thrombosis (DVT) or Pulmonary Embolism (PE).
Timepoint [1] 333053 0
Identified during days 30 and 90 post-surgery (primary endpoint) by follow-up phone call and confirmed by USS or imaging.
Secondary outcome [1] 415642 0
• Quality of Life –EQ-5D
The EQ-5D is a brief survey of health status covering 5 domains: mobility, self-care, usual activities, pain/discomfort and anxiety/depression
Timepoint [1] 415642 0
Baseline (pre-surgery), day 30 and day 90 post-surgery.
Secondary outcome [2] 415643 0
• The WHODAS-12: the WHO’s International Classification of Functioning, Disability and Health (ICF) including the 6 domains; cognition, mobility, self-care, getting along, life activities, & participation. This will be used to capture potential inpatient and outpatient functional disturbances as a result of IPCDs.
Timepoint [2] 415643 0
Baseline (pre-surgery), day 30 and day 90 post-surgery.
Secondary outcome [3] 415644 0
Sleep questionnaire- PROMIS
The PROMIS assessment tool has extensive PROM item banks that cover a wide range of conditions, symptoms and symptom areas broadly grouped under mental health, physical health, and social health. We will be using one of the item banks under physical health, the PROMIS-SF, to assess sleep disturbance, based on feedback received concerning sleep disturbance in our pilot study
Timepoint [3] 415644 0
Baseline, the night before surgery, every day until discharge and at day 30 and day 90 post-surgery.
Secondary outcome [4] 415645 0
• The Inpatient PREM question set available from the NSW Agency for Clinical Innovation (Inpatient PREM questions (nsw.gov.au)) to capture patients’ perception of their experience during their inpatient stay.
Timepoint [4] 415645 0
Discharge
Secondary outcome [5] 415646 0
Compliance with wearing IPCDs,
Timepoint [5] 415646 0
Daily diary record by the patient of how many hours the long the IPCDS were not worn and twice daily checking by the research nurse.
Secondary outcome [6] 415647 0
Overall mortality
Timepoint [6] 415647 0
By accessing medical records up to day 90 post surgery
Secondary outcome [7] 415648 0
Clavien-Dindo classification- post-surgical complications by accessing medical records
Timepoint [7] 415648 0
During hospital admission and at days 30 and 90 post-surgery
Secondary outcome [8] 415649 0
IPCD-related complications (e.g. neuropathy, rash, compartment syndrome) are assessed by participant self-report, physical examination and documentation in medical records.
Timepoint [8] 415649 0
During admission and at days 30 and 90 post-surgery.
Secondary outcome [9] 415650 0
Bleeding complications (e.g. gastrointestinal bleeding, intracranial bleeding, intrabdominal bleeding) are assessed by accessing medical records and daily checks of patients by the research nurse.
Timepoint [9] 415650 0
Monitored continuously from the time of surgery to the time of hospital discharge.
Secondary outcome [10] 415703 0
Healthcare resource use by accessing Medicare Benefits Scheme (MBS) database, as reported by participants in the day 30 and 90 follow-up phone calls and via medical records.
Timepoint [10] 415703 0
At the end of the trial when the last participants reach the 90 day follow up
Secondary outcome [11] 416500 0
Compliance with wearing the graduated compression stockings.
Timepoint [11] 416500 0
Daily diary record by the patient of how many hours the GCS were not worn and checking by the research nurse.
Secondary outcome [12] 416501 0
Compliance with the administration of Clexane
Timepoint [12] 416501 0
Compliance will be monitored by either the paper or digital medication record daily.
Secondary outcome [13] 416502 0
Clinical symptoms of DVT by physical examination and documentation in medical records during hospital or with participants' General Practitioner post-discharge from the hospital.
Timepoint [13] 416502 0
Monitored throughout the hospital stay and at days 30 and 90 post-surgery.
Secondary outcome [14] 416503 0
Clinical symptoms of PE by physical examination, documentation in medical records during hospital or with participants' General Practitioner post-discharge from the hospital.
Timepoint [14] 416503 0
Monitored throughout the hospital stay and at days 30 and 90 post-surgery.
Secondary outcome [15] 416504 0
Length of stay (LOS) as documented in medical records
Timepoint [15] 416504 0
Data collected at days 30 and day 90 post-surgery.
Secondary outcome [16] 416505 0
Days alive and out of hospital as documented in medical records.
Timepoint [16] 416505 0
Data collected at days 30 and day 90 post-surgery.
Secondary outcome [17] 416506 0
Emergency department presentations related to VTE s documented in medical records.
Timepoint [17] 416506 0
Data collected at days 30 and day 90 post-surgery.
Secondary outcome [18] 416507 0
Hospital admissions related to VTE as documented in medical records.
Timepoint [18] 416507 0
Data collected at days 30 and day 90 post-surgery.

Eligibility
Key inclusion criteria
• Patient undergoing elective major surgery with major surgery defined as any operation deemed by the surgical team to be requiring admission to hospital beyond 24 hours
• >18 years of age
• Moderate or high risk of venous thromboembolism (VTE) based on NSW risk assessment form
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Are unable to give written informed consent to take part in the study
• are not expected to be ambulant within 24 hours
• Have contraindications to LMWH
• Have contraindications to GCS or IPCDs
• Have had previous heparin-induced thrombocytopenia/thrombosis (HITT)
• are undergoing lower leg surgery (orthopaedics)
• Have active, clinically significant bleeding (Class 2 and above) i.e. volume loss of 15% to over 40% of total blood volume.
• Have documented congenital or acquired bleeding tendency/disorders
• Have had a recent intracranial haemorrhage or recent (less than 3 months prior to randomization) brain spinal, or ophthalmologic surgery
• Have epidural or spinal anaesthesia planned
• Have active peptic ulcer or treatment of same in the last three months
• Have severe liver disease (Liver cirrhosis)
• Have current thrombocytopenia e.g., platelets <70
• Have renal Impairment GFR <30 and or creatinine level above 2.0 mg/dL (180 µmol/L) in a well-hydrated participant
• Are pregnant and/or breastfeeding women
• Have evidence of leg ischemia caused by peripheral vascular disease (previously documented or on clinical assessment)
• Have clinical signs of VTE and/or a history of VTE- Pulmonary embolism, Deep vein thrombosis
• Have pre-existing indications for heparins (including LMWH). These are people at a high risk of getting clots, to reduce their chances of developing serious conditions such as strokes and heart attacks ie Atrial fibrillation, Pulmonary hypertension, Cardiomyopathy, Ischemic stroke, Certain congenital heart disorders, Artificial valve replacement

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation involves the research nurse at each site logging onto a password-protected database and contacting the holder of the allocation schedule who was "off-site" or at central administration site.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
The sample size is based on data from the GAPS trial (UK) on similar risk surgical inpatients. The day 30 VTE rates in this trial were 1.4 and 1.7% for the control and intervention groups. We have assumed a slightly higher rate of 2.5% to adjust for the fact that the cohort will be at a slightly higher VTE risk via inclusion criteria. We have performed a bi-national (Australia and New Zealand) survey of surgeons that undertake high risk abdominal surgery and found that 100% of them would not use IPCDs if they provided less than a 2% reduction in VTE rates. We have therefore chosen a non-inferiority margin of 1.5%.

To determine the sample size and corresponding frequentist operating characteristics, we simulated data for both stages of the trial (interim and final). We considered two scenarios: 1) when the true proportions equal 2.5% (to assess power to declare non-inferiority) and 2) when the proportion in the intervention group was unacceptably higher than the control group (4.5% vs 2.5%). In both scenarios, we used a non-inferiority margin of 1.5%. The decision threshold to stop the trial for futility at the interim analysis was based on the posterior predicted probability of declaring non-inferiority at the end of the trial (trials being stopped for futility if this was 27.5% or lower). The decision threshold to declare non-inferiority at the final stage was based on the posterior probability that the difference was less than the NIM (non-inferiority declared if this probability exceeded a threshold of 90%). A final stage sample size of 1856 per group enables the study to correctly declare non-inferiority with 90% probability, and correctly declare futility at the interim analysis with 80% probability. The rate of incorrectly declaring non-inferiority (at the final stage) was 1% and incorrectly stopping the trial early (at the interim analysis) was 3%.

Analysis population: The full analysis population is all eligible participants that were randomised to receive an intervention.

We will compare the primary outcome (day 30 VTE) between groups in the full analysis population according to their randomised treatment group. We will use a Bayesian model for estimating the difference in proportions between groups, where we assume the outcome data within each group follows a binomial distributions and the parameters of these distributions (corresponding to the probability of a VTE event) follow Beta(1,1) distributions (corresponding to uninformative uniform priors). The posterior distribution for the probability of a VTE in the intervention group will therefore follow a beta distribution, with parameters 1+ x1, and 1 + n1 – x1, where x1 is the corresponding number of events in that group and n1 the sample size for that group (the posterior distribution in the control group is analogous). Assuming the trial gets to the final stage, then we will estimate the probability that the difference in these probabilities is < NIM, and declare non-inferiority if this probability exceeds 95%. Missing data will be drawn from the posterior predictive distribution within this Bayesian framework.

Interim analysis: After 50% of the patients have been recruited the posterior predictive probability of declaring non-inferiority at the final stage will be estimated from the same Bayesian model described above. If this probability is less than 35%, then futility will be declared, and the trial will be considered for stopping due to safety reasons (as this will indicate the removing the intervention has a higher VTE probability than usual care).

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/05/2023
Actual
1/05/2023
Date of last participant enrolment
Anticipated
20/12/2025
Actual
Date of last data collection
Anticipated
20/03/2026
Actual
Sample size
Target
4130
Accrual to date
47
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment postcode(s) [1] 38930 0
2305 - New Lambton Heights
Recruitment postcode(s) [2] 38931 0
2444 - Port Macquarie
Recruitment postcode(s) [3] 38932 0
2340 - Tamworth
Recruitment postcode(s) [4] 38933 0
2250 - Gosford
Recruitment postcode(s) [5] 38934 0
2298 - Waratah West

Funding & Sponsors
Funding source category [1] 312612 0
Government body
Name [1] 312612 0
NSW Health
Country [1] 312612 0
Australia
Primary sponsor type
University
Name
University of Newcastle
Address
University Dr, Callaghan NSW 2308
Country
Australia
Secondary sponsor category [1] 314221 0
None
Name [1] 314221 0
Address [1] 314221 0
Country [1] 314221 0
Other collaborator category [1] 282481 0
Other Collaborative groups
Name [1] 282481 0
Hunter Medical Research Institute
Address [1] 282481 0
Lot 1 Kookaburra Cct, New Lambton Heights NSW 2305
Country [1] 282481 0
Australia
Other collaborator category [2] 282482 0
Hospital
Name [2] 282482 0
John Hunter Hospital
Address [2] 282482 0
Lookout Rd, New Lambton Heights NSW 2305
Country [2] 282482 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311939 0
Hunter New England Human Research Ethics Committee
Ethics committee address [1] 311939 0
Ethics committee country [1] 311939 0
Australia
Date submitted for ethics approval [1] 311939 0
24/10/2022
Approval date [1] 311939 0
30/11/2022
Ethics approval number [1] 311939 0
2022/ETH02276

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 122890 0
Prof Stephen Smith
Address 122890 0
John Hunter Hospital,
Locked Bag No 1,
Hunter Region Mail Centre
NSW 2310
Australia
Country 122890 0
Australia
Phone 122890 0
+61 418215968
Fax 122890 0
+61 (02) 4921 4274
Email 122890 0
[email protected]
Contact person for public queries
Name 122891 0
Natalie Lott
Address 122891 0
John Hunter Hospital,
Locked Bag No 1,
Hunter Region Mail Centre
NSW 2310
Australia
Country 122891 0
Australia
Phone 122891 0
+61 418215968
Fax 122891 0
+61 (02) 4921 4274
Email 122891 0
[email protected]
Contact person for scientific queries
Name 122892 0
Natalie Lott
Address 122892 0
John Hunter Hospital,
Locked Bag No 1,
Hunter Region Mail Centre
NSW 2310
Australia
Country 122892 0
Australia
Phone 122892 0
+61 418215968
Fax 122892 0
+61 (02) 4921 4274
Email 122892 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Sensitive data


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.