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Trial registered on ANZCTR


Registration number
ACTRN12619000339156
Ethics application status
Approved
Date submitted
15/02/2019
Date registered
5/03/2019
Date last updated
6/12/2019
Date data sharing statement initially provided
5/03/2019
Date results information initially provided
29/03/2019
Type of registration
Retrospectively registered

Titles & IDs
Public title
Optimisation of the use of tranexamic acid, a medication used to treat or prevent excessive blood loss during total knee replacement surgery
Scientific title
A prospective, randomised non-blinded pilot study to optimise oral tranexamic acid dosing in primary total knee arthroplasty
Secondary ID [1] 297407 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
osteoarthritis 311567 0
total knee arthroplasty 311568 0
Condition category
Condition code
Musculoskeletal 310198 310198 0 0
Osteoarthritis
Surgery 310199 310199 0 0
Other surgery

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The dosage and frequency of dosing of tranexamic acid for each participant will be determined by a personalised dosing algorithm developed specifically for this study. A Shiny application calculator based on a published population pharmacokinetic model (Lanoiselee, J., et al., Is tranexamic acid exposure related to blood loss in hip arthroplasty? A pharmacokinetic-pharmacodynamic study. Br J Clin Pharmacol, 2018. 84(2): p. 310-319.) and pharmacokinetic information for oral TXA (Pilbrant, A., M. Schannong, and J. Vessman, Pharmacokinetics and bioavailability of tranexamic acid. Eur J Clin Pharmacol, 1981. 20(1): p. 65-72.), has been developed to display the median expected concentration-time profile after dosing of oral TXA. Participant characteristics, such as total body weight, sex, age, serum creatinine are variables that affect the PK of TXA and can be specifically set in the Shiny application for each individual participant. This will then tailor the median expected concentration-time profile after dosing of oral TXA towards the entered participant characteristics. Different dosing intervals and the number of days of treatment to which a participant would be randomised as part of the study can also be set by a user of the application. The tranexamic acid comes in the form of a 500 mg tablet which will be titrated and prescribed to the participant in line with the algorithm result.
Group 1 – Participants will receive an individualised oral dose of tranexamic acid one hour prior to total knee replacement surgery
Group 2 – Participants will receive an individualised oral dose of tranexamic acid one hour prior to surgery and continue individualised tranexamic acid to maintain therapeutic plasma tranexamic acid levels (10 – 50 mg/L) for 24 hours following total knee replacement surgery.
Group 3 - Participants will receive an individualised oral dose of tranexamic acid one hour prior to surgery and continue individualised tranexamic to maintain therapeutic plasma tranexamic levels (10 – 50 mg/L) for 72 hours following total knee replacement surgery.
Intervention code [1] 313656 0
Treatment: Drugs
Comparator / control treatment
Dose comparison
Control group
Dose comparison

Outcomes
Primary outcome [1] 319087 0
Time to consistently achieve 90 degrees of knee flexion. Range of motion/flexion will be measured using a double-armed goniometer by the number of degrees from the starting position of the knee joint to its position at the end of its full range of the movement.
Timepoint [1] 319087 0
The change in range of motion measured daily from pre-surgery (day 0) to day 4 post-surgery will be recorded as a percentage change. The post-operative day on which the participant achieves 90 degrees of knee flexion will be recorded. If the participant is discharged prior to achieving 90 degrees flexion, the participant will be followed up via telephone. These participants will be assessed by an outpatient physiotherapist until 90 degrees flexion is documented.
Primary outcome [2] 319088 0
Maximum change in knee girth in cm as a percentage increase. Participants will have leg girth measured (at mid-patellar level) before surgery and once the bandages have been removed using a paper tape measure whilst in lying position.
Timepoint [2] 319088 0
Measurements will be on admission and in the morning of days 1, 2, 3 and 4 post-operatively.
Primary outcome [3] 319142 0
Quality of life measured using Oxford Knee Score
Timepoint [3] 319142 0
Participants will be complete the assessment in writing pre-operatively and over the telephone at 6 weeks and 6 months post-operatively.
Secondary outcome [1] 366952 0
Blood loss as assessed by blood sample assay for haemoglobin
Timepoint [1] 366952 0
Calculated as difference between admission haemoglobin (Hb) and lowest post-operative Hb during hospital stay or prior to blood transfusion.
Secondary outcome [2] 366953 0
Pain (using verbal pain score)
Timepoint [2] 366953 0
Measured each day whilst in hospital prior to discharge

Eligibility
Key inclusion criteria
- participants of either sex scheduled to undergo a primary, unilateral TKA (either anterior or posterior approach, but not joint resurfacing)
- available for follow up at 6 months post-surgery
- willingness to provide written, informed consent
- willingness to comply with the study
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- known allergy to TXA
- acquired disturbances to colour vision
- preoperative use of anticoagulants (within 5 days of surgery)
- fibrinolytic disorders requiring intraoperative fibrinolytics
- coagulopathy, history of arteriolar or venous thromboembolic disease
- pregnancy or breastfeeding
- hepatic failure
- haemoglobin <10g/dL

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Not Applicable
Type of endpoint(s)
Statistical methods / analysis
The primary outcomes are time to consistently achieve 90 degrees flexion and the maximal change in knee girth as a percentage increase. Secondary outcomes include blood loss (defined as the difference between the pre-operative Hb and the lowest Hb, be that the day 4 Hb or the Hb prior to transfusion), daily pain scores and change in Oxford Knee Score. The comparisons of interest are between group 1 and group 2, group 1 and group 3 and group 2 and group 3. Categorical variables will be examined using a Pearson Chi-squared test or Fisher’s Exact test. Continuous variables will be examined using a one-way anova or Kruskal-Wallis test. A p-value <0.05 will be considered statistically significant.

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)
QLD
Recruitment hospital [1] 13140 0
The Wesley Hospital - Auchenflower
Recruitment postcode(s) [1] 25682 0
4066 - Auchenflower

Funding & Sponsors
Funding source category [1] 301977 0
Charities/Societies/Foundations
Name [1] 301977 0
Wesley Medical Research
Address [1] 301977 0
Level 8, The Wesley Hospital, 451 Coronation Drive, Auchenflower, Queensland, 4066
Country [1] 301977 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
Wesley Medical Research
Address
Level 8, The Wesley Hospital, 451 Coronation Drive, Auchenflower, Queensland, 4066
Country
Australia
Secondary sponsor category [1] 301751 0
None
Name [1] 301751 0
Address [1] 301751 0
Country [1] 301751 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302656 0
UnitingCare Health Human Research Ethics Committee
Ethics committee address [1] 302656 0
The Wesley Hospital
PO Box 499
Auchenflower Qld 4066
Ethics committee country [1] 302656 0
Australia
Date submitted for ethics approval [1] 302656 0
Approval date [1] 302656 0
19/05/2017
Ethics approval number [1] 302656 0
1714

Summary
Brief summary
Total knee replacement (TKR) is a major surgical operation that will be conducted in increasing numbers in Australia over the next 10 years. The patient’s post-operative course is typically painful and can have significant associated morbidity. The recovery process is also expensive due to the intensive nursing and physiotherapy that are required for rehabilitation. Optimising and streamlining this clinical pathway is vital for improved patient outcomes and the overall health budget.

Whilst there is evidence to support the early mobilisation of patients post TKR (to reduce venous thromboembolism (VTE)), respiratory complications and bowel dysfunction), this may cause bleeding in and around the joint. This blood creates swelling, pain, reduced mobility, decreased knee flexion and an increased potential for infection. The primary goal of this study is to decrease surgical site bleeding as the patient mobilises in the early post-operative period. We aim to assess this by a number of clinical outcome measures.

The study will use oral tranexamic acid (TXA) to reduce post-operative bleeding. It is already accepted that TXA is effective in reducing blood loss for TKR, whether it is used in the intravenous, topical or oral route. Current literature shows that there have been no attempts in individualising oral dosing of TXA for a patient, based on their weight and renal function. Additionally, evidence is sparse regards to identifying the benefits of achieving acceptable therapeutic target TXA exposure in plasma over a longer period while the potential for bleeding at the surgical site to occur is still high. We aim to show that therapeutic exposure of TXA can be used safely over a prolonged period and that this will improve outcomes.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 90954 0
Dr Sue Clark
Address 90954 0
Wesley Anaesthesia and Pain Management
Suite 17, level 2
Wesley Medical Centre
17/40 Chasely St
AUCHENFLOWER QLD 4066
Country 90954 0
Australia
Phone 90954 0
+61 7 3377 0500
Fax 90954 0
Email 90954 0
susieclark@me.com
Contact person for public queries
Name 90955 0
Dr Kelley Foster
Address 90955 0
Wesley Medical Research, Level 8, The Wesley Hospital, 451 Coronation Drive, Auchenflower, Queensland 4066
Country 90955 0
Australia
Phone 90955 0
+61737211503
Fax 90955 0
Email 90955 0
kfoster@wesleyresearch.com.au
Contact person for scientific queries
Name 90956 0
Dr Kelley Foster
Address 90956 0
Wesley Medical Research, Level 8, The Wesley Hospital, 451 Coronation Drive, Auchenflower, Queensland 4066
Country 90956 0
Australia
Phone 90956 0
+61737211503
Fax 90956 0
Email 90956 0
kfoster@wesleyresearch.com.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary