Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000182796
Ethics application status
Approved
Date submitted
21/12/2021
Date registered
2/02/2022
Date last updated
8/09/2024
Date data sharing statement initially provided
2/02/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
The feasibility of a personalized approach to venous thromboembolism prophylaxis in heavier critically ill patients.
Scientific title
The feasibility of a personalized approach to venous thromboembolism prophylaxis in heavier critically ill patients.
Secondary ID [1] 306086 0
None.
Universal Trial Number (UTN)
Trial acronym
PROSPER
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Critical illness 324745 0
Venous thromboembolism 324746 0
Condition category
Condition code
Blood 322198 322198 0 0
Clotting disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention treatment offers an alternative approach to the dosing regimen of venous thromboembolism (VTE) chemoprophylaxis. Patients assigned to the intervention arm will
receive enoxaparin according to a personalized algorithm based on the patient's body weight and guided by the anti-Xa levels.
The weight-based dosing with dynamic adjustment regimen will be as follows:
1.) Enoxaparin initial dosing will be based on patient's body weight at ICU admission (~0.5mg/kg twice daily).
If a patient weighs 100-119kg, the initial dose will be 50 mg subcutaneously (SC) twice daily.
If a patient weighs 120-139kg, the initial dose will be 60 mg SC twice daily.
If a patient weighs 140-159kg, the initial dose will be 70 mg SC twice daily.
If a patient weighs 160-179kg, the initial dose will be 80 mg SC twice daily.
If a patient weighs 180kg, the initial dose will be 90 mg SC twice daily.
Adherence to the intervention will be monitored through the patients' electronic medical record.
2.) The peak anti-Xa level will be determined from a blood sample drawn 4 hours after the third dose has been administered.
3.) Enoxaparin dose will be adjusted according to the anti-Xa level.
If the peak anti-Xa level is below 0.2 IU/mL, the dose will be increased by 10mg SC twice daily.
If the peak anti-Xa level is between 0.2 - 0.4 IU/mL, the dose will not change as this is the recommended prophylactic range for peak anti-Xa levels.
If the peak anti-Xa level is between 0.41 - 0.59 IU/mL, the dose will be decreased by 10mg SC twice daily.
If the peak anti-Xa level is equal to or greater than 0.6 IU/mL, the dose will be decreased by 20mg SC twice daily.
120mg SC twice daily will be the maximum dose administered.
4.) The anti-Xa assay will be repeated for every three doses of enoxaparin administered.

The total duration of administration will be 28 days from randomization provided that patient is still in ICU and remains eligible for the study. If a patient meets one of the following, they are no longer eligible for the study, therefore the administration of the study drug will cease:
1. The treating Intensivist believes a particular VTE chemoprophylaxis regimen is indicated at any stage, in which case they can override the treatment allocation and this will be recorded as a protocol violation.
2. The patient develops acute kidney injury (defined as eGFR < 30 ml/min). In such cases dosing will revert to 40 mg SC daily (or as advised by intensivist) with no further anti-Xa levels recorded
3. There is a need for therapeutic anticoagulation
4. There is no arterial or venous catheter for clinical purposes, such that blood for anti-Xa level cannot be obtained. In such cases dosing will revert to 40 mg SC twice daily.

The route of administration of enoxaparin is subcutaneously (SC).
Intervention code [1] 322495 0
Prevention
Comparator / control treatment
The standard care for venous thromboembolism (VTE) chemoprophylaxis in patients weighing equal to or greater than 100kg is a fixed dose approach of enoxaparin 40 mg subcutaneously (SC) twice daily and intermittent (ad-hoc) measuring of effect (anti-Xa levels).
The total duration of administration will be 28 days from randomization provided that patient is still in ICU and the following does not eventuate:
1. The treating Intensivist believes a particular VTE chemoprophylaxis regimen is indicated at any stage, in which case they can override the treatment allocation and this will be recorded as a protocol violation.
2. There is a need for therapeutic anticoagulation.
Control group
Active

Outcomes
Primary outcome [1] 329960 0
The primary outcome measure is feasibility of the weight-based dosing with dynamic adjustment.
The feasibility threshold will be set at 5% of anti-Xa levels reaching therapeutic levels (i.e. if the percentage of anti-Xa levels 0.6 IU/mL is less than 5 % of recorded values) the intervention will be deemed feasible. Anti-Xa levels are determined by blood samples drawn.
Timepoint [1] 329960 0
Measured throughout the entire duration of the patient's stay in ICU.
Secondary outcome [1] 404447 0
Feasibility outcome: Time in anti-Xa prophylactic level range (0.2 to 0.4 IU/mL). Method of assessment is anti-Xa assay from patients' blood sample.
Timepoint [1] 404447 0
Measured throughout the entire duration of the patient's stay in ICU.
Secondary outcome [2] 404448 0
Feasibility outcome: The number of doses that are administered that are ‘incorrect’ according to algorithm. Method of assessment is the patients' medical record.
Timepoint [2] 404448 0
Measured throughout the entire duration of the patient's stay in ICU.
Secondary outcome [3] 404449 0
Bleeding complications (defined as minor if VTE chemoprophylaxis dose held or reduced, and major if accompanied by transfusion or operation) that occur in ICU. Method of assessment is patients' medical record.
Timepoint [3] 404449 0
Measured throughout the entire duration of the patient's stay in ICU.
Secondary outcome [4] 404450 0
Thrombosis – deep venous thrombosis and pulmonary embolism that occur in hospital and censored at day 90 from enrolment. Method of assessment is patients' medical record.
Timepoint [4] 404450 0
Duration of patient's hospital stay, censored at day 90 from enrolment.
Secondary outcome [5] 404451 0
Routine biochemical data: APPT/INR from blood samples when collected in ICU and reported as highest daily and censored at day 14 from enrolment. Method of assessment is patients' medical record, no additional biochemical data will be requested for the study other than what is collected and entered into the medical record as part of standard care.
Timepoint [5] 404451 0
Patient's stay in ICU, censored at day 14 from enrolment.
Secondary outcome [6] 404452 0
Routine biochemical data: Platelet count from blood samples when collected in ICU and reported as lowest daily and censored at day 14 from enrolment. Method of assessment is patients' medical record, no additional biochemical data will be requested for the study other than what is collected and entered into the medical record as part of standard care.
Timepoint [6] 404452 0
Patient's duration in ICU, censored at day 14 from enrolment.
Secondary outcome [7] 404453 0
Routine biochemical data: Haemoglobin determined from blood samples when collected in ICU and reported as lowest daily and censored at day 14 from enrolment. Method of assessment is patients' medical record, no additional biochemical data will be requested for the study other than what is collected and entered into the medical record as part of standard care.
Timepoint [7] 404453 0
Patient's stay in ICU, censored at day 14 from enrolment.
Secondary outcome [8] 404454 0
Duration of ICU admission, assessed by patient medical records.
Timepoint [8] 404454 0
Patient discharge from ICU.
Secondary outcome [9] 404455 0
Mortality, assessed by information in patients' medical records.
Timepoint [9] 404455 0
90 days from enrolment.
Secondary outcome [10] 405386 0
Duration of hospital admission, assessed by patient medical records.
Timepoint [10] 405386 0
Patient discharge from hospital.

Eligibility
Key inclusion criteria
I. Adult patients greater than or equal to 18 years of age
II. Admitted to RMH ICU
III. Admission weight recorded as greater than or equal to 100 kg
IV. Suitable to receive VTE chemoprophylaxis with enoxaparin (a Low Weight Molecular Heparin)
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
I. Renal impairment that would cause a reduction in chemoprophylaxis dosing (eGFR < 30 ml/min).
II. Admitted after cardiac- neuro- or spinal surgery
III. Pregnancy
IV. Abnormal baseline coagulation (INR >1.5 or APTT >60 sec or platelets <50 × 109/L)
V. Require therapeutic anti-coagulation
VI. Treating intensivist believes either a fixed dose (40mg BD) OR weight-based dynamic adjustment dosing regimen is required for that patient.
VII. Received > 3 doses of enoxaparin in this ICU admission

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 is not concealed.
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
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Small pilot studies are by definition underpowered to detect many clinically important differences between the treatment arms. Thus the statistical focus of pilot trials should be on descriptive statistics (means, proportions, medians) and their associated confidence intervals or quantile ranges, rather than formal hypothesis testing, to provide an estimate of possible treatment effects. Pilot studies may usefully help assess minimum clinically important differences even if confidence intervals reported are numerically less than 95% (such as 85% or 75%) (29). We will conduct this trial over a 12 month period. Based on our audit we anticipate that over a 12-month period greater than 520 patients weighing equal to or greater than 100 kg will be admitted. A conservative estimate is that 50% of patients will meet all inclusion criteria and no exclusion criterion providing a minimum of 260 patients to be enrolled.


Statistical methods will be led by Dr Emily Karahalios (Biostatistician with Methods and Implementation Support for Clinical and Health Research Hub, MISCH) with analyses conducted using Stata.
Descriptive statistics will be presented for each trial arm and overall. Feasibility outcomes will be presented as proportion or time as per unit variable. Normally distributed data will be presented as means and standard deviations, skewed data presented as medians and interquartile ranges, counts as number (%).
We will conduct inferential statistical testing using unpaired Student’s t-test for biochemical and clinical outcomes with no adjustment for multiple comparisons. All data will be retained for intention to treat analysis. We will conduct a subgroup analyses in cohorts of: 1. patients who receive at least 4 doses of enoxaparin in ICU; and 2. Admission weight is equal to 150 kg.

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
1/03/2022
Actual
21/03/2022
Date of last participant enrolment
Anticipated
1/03/2023
Actual
24/02/2023
Date of last data collection
Anticipated
1/01/2025
Actual
Sample size
Target
260
Accrual to date
Final
53
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 21390 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment postcode(s) [1] 36279 0
3050 - Parkville

Funding & Sponsors
Funding source category [1] 310429 0
Hospital
Name [1] 310429 0
Royal Melbourne Hospital
Country [1] 310429 0
Australia
Primary sponsor type
Hospital
Name
Royal Melbourne Hospital
Address
300 Grattan St
Parkville, 3050
VIC
Country
Australia
Secondary sponsor category [1] 311584 0
None
Name [1] 311584 0
Address [1] 311584 0
Country [1] 311584 0
Other collaborator category [1] 282114 0
University
Name [1] 282114 0
University of Melbourne
Address [1] 282114 0
The University of Melbourne
207 Bouverie Street
Parkville, 3010
VIC
Country [1] 282114 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310066 0
Royal Melbourne Hospital Human Research Ethics Committee
Ethics committee address [1] 310066 0
Ethics committee country [1] 310066 0
Australia
Date submitted for ethics approval [1] 310066 0
07/09/2021
Approval date [1] 310066 0
27/09/2021
Ethics approval number [1] 310066 0
HREC/78209/MH-2021

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

Contacts
Principal investigator
Name 116374 0
A/Prof Adam Deane
Address 116374 0
The Royal Melbourne Hospital, Intensive Care Unit
300 Grattan Street,
Parkville. 3050
VIC
Country 116374 0
Australia
Phone 116374 0
+61 3 9342 9254
Fax 116374 0
Email 116374 0
[email protected]
Contact person for public queries
Name 116375 0
Brianna Tascone
Address 116375 0
The Royal Melbourne Hospital, Intensive Care Unit
300 Grattan Street,
Parkville 3050
VIC
Country 116375 0
Australia
Phone 116375 0
+61 393429252
Fax 116375 0
Email 116375 0
[email protected]
Contact person for scientific queries
Name 116376 0
Brianna Tascone
Address 116376 0
The Royal Melbourne Hospital, Intensive Care Unit
300 Grattan Street,
Parkville 3050
VIC
Country 116376 0
Australia
Phone 116376 0
+61 393429252
Fax 116376 0
Email 116376 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Individual data underlying results only.
When will data be available (start and end dates)?
After publication. No end date.
Available to whom?
Decided by Principal Investigator upon request.
Available for what types of analyses?
Any purpose approved by Principal Investigator upon request.
How or where can data be obtained?
Upon request from Principal Investigator through emailing:
[email protected]


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.