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Trial registered on ANZCTR


Registration number
ACTRN12623000340639
Ethics application status
Approved
Date submitted
22/03/2023
Date registered
31/03/2023
Date last updated
16/04/2024
Date data sharing statement initially provided
31/03/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Budesonide versus prednisolone after liver transplantation: a phase 3, open label, non-inferiority randomised controlled trial
Scientific title
Budesonide versus prednisolone after liver transplantation: a phase 3, open label, non-inferiority randomised controlled trial
Secondary ID [1] 309272 0
None
Universal Trial Number (UTN)
Trial acronym
BRAVE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Liver transplantation 329426 0
Allograft rejection 329427 0
Condition category
Condition code
Oral and Gastrointestinal 326375 326375 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
Surgery 326478 326478 0 0
Other surgery

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Intervention ('Budesonide Arm'): oral tablet budesonide 9mg daily between day 3 to day 14 post liver transplantation, weaned to oral tablet budesonide 6mg daily at week 3 post liver transplantation, then oral budesonide 3mg daily at week 5 post liver transplantation and then ceased at end of week 6 post liver transplantation. After the 6 week course of budesonide, patients will return any leftover medication to the Clinical Trials Pharmacy for counting and assessment of adherence.

Patients in both the Control Arm and the Budesonide Arm will receive a single dose of intravenous methylprednisolone intra-operatively followed by intravenous methylprednisolone 16mg daily on days 1 and 2 following liver transplantation. Other concomitant immunosuppression will be continued in both the Control and Budesonide Arms based on stratification by renal function, as per standard of care. Patients with impaired renal function (e.g. creatinine >120mg/dL or hepatorenal syndrome requiring terlipressin) will receive intravenous basiliximab 20mg on days 1 and 4 following liver transplant, and then receive oral tablet tacrolimus twice daily with dose titrated to drug trough levels. Patients with normal renal function will receive oral tablet tacrolimus twice daily with dose titrated to drug trough levels. All patients will receive mycophenolate mofetil 1g twice daily, except for patients with primary sclerosing cholangitis as the underlying aetiology of liver disease, who received weight-based azathioprine (typically azathioprine 100mg daily). Medications will be administered intravenously until the patient is able to tolerate oral intake.
Intervention code [1] 325709 0
Treatment: Drugs
Intervention code [2] 325710 0
Prevention
Comparator / control treatment
Control ('Control Arm'): oral tablet prednisolone 20mg daily between day 3 to day 14 post liver transplantation, weaned to oral tablet prednisolone 15mg daily at week 3 post liver transplantation, then oral tablet prednisolone 10mg daily at week 4 post liver transplantation, then oral tablet prednisolone 5mg daily at week 5 post liver transplantation and then ceased at end of week 6 post liver transplantation. After the 6 week course of prednisolone, patients will return any leftover medication to the Clinical Trials Pharmacy for counting and assessment of adherence.

Patients in both the Control Arm and the Budesonide Arm will receive a single dose of intravenous methylprednisolone intra-operatively followed by intravenous methylprednisolone 16mg daily on days 1 and 2 following liver transplantation. Other concomitant immunosuppression will be continued in both the Control and Budesonide Arms based on stratification by renal function, as per standard of care. Patients with impaired renal function (e.g. creatinine >120mg/dL or hepatorenal syndrome requiring terlipressin) will receive intravenous basiliximab 20mg on days 1 and 4 following liver transplant, and then receive oral tablet tacrolimus twice daily with dose titrated to drug trough levels. Patients with normal renal function will receive oral tablet tacrolimus twice daily with dose titrated to drug trough levels. All patients will receive mycophenolate mofetil 1g twice daily, except for patients with primary sclerosing cholangitis as the underlying aetiology of liver disease, who received weight-based azathioprine (typically azathioprine 100mg daily). Medications will be administered intravenously until the patient is able to tolerate oral intake.
Control group
Active

Outcomes
Primary outcome [1] 334225 0
Rate of liver biopsy-proven acute cellular rejection. Acute cellular rejection defined as a Banff Rejection Activity Index score of 4 or above on histology of liver biopsy.
Timepoint [1] 334225 0
Within 90 days post liver transplantation
Secondary outcome [1] 419894 0
Corticosteroid-related side effects (behavioural change, cognitive or mood disturbance, insomnia, corticosteroid-related cutaneous changes).
Timepoint [1] 419894 0
At weeks 1, 2, 3, 4, 5, 6 and at 3, 6, 9 and 12 months post liver transplant.
Secondary outcome [2] 419895 0
Incidence of infection (bacterial, viral, fungal) as documented in electronic medical records.
Timepoint [2] 419895 0
At weeks 1, 2, 3, 4, 5, 6, and at 3, 6, 9 and 12 months post liver transplant.
Secondary outcome [3] 419896 0
Assessment of whole blood immune function as measured by Quantiferon Monitor Assay.
Timepoint [3] 419896 0
At weeks 1, 2, 3, 4, 5, 6, and at 3 months post liver transplant.
Secondary outcome [4] 419897 0
Incidence of wound complications (dehiscence, incisional hernia) as documented in patient's medical record.
Timepoint [4] 419897 0
At weeks 1, 2, 3, 4, 5, 6, and at 3, 6, 9 and 12 months post liver transplant.
Secondary outcome [5] 419898 0
Incidence of biliary complications (e.g. choledocholithiasis, bile leak, anastomotic stricture) as documented in electronic medical records.
Timepoint [5] 419898 0
At weeks 1, 2, 3, 4, 5, 6, and at 3, 6, 9 and 12 months post liver transplant.
Secondary outcome [6] 419899 0
Graft injury as measured by hepatocyte-specific methylation in cell-free DNA obtained from plasma samples.
Timepoint [6] 419899 0
At weeks 1, 2, 3, 4, 5, 6, and at 3 months post liver transplant.
Secondary outcome [7] 419900 0
Incidence of new onset diabetes after transplant as documented in electronic medical records.
Timepoint [7] 419900 0
At 3, 6, 9 and 12 months post liver transplant.
Secondary outcome [8] 419901 0
Change in fasting glucose levels obtained from blood tests
Timepoint [8] 419901 0
At enrolment, at weeks 1, 2, 3, 4, 5, 6 and at 3, 6, 9, 12 months post liver transplant.
Secondary outcome [9] 419902 0
Change in fasting insulin levels obtained from blood tests
Timepoint [9] 419902 0
At enrolment and at 3, 6, 9, 12 months post liver transplant.
Secondary outcome [10] 419903 0
Change in HbA1c levels obtained from blood tests
Timepoint [10] 419903 0
At enrolment and at 3, 6, 9, 12 months post liver transplant.
Secondary outcome [11] 419904 0
Change in fasting lipid profile obtained from blood tests
Timepoint [11] 419904 0
At enrolment and at 3, 6, 9, 12 months post liver transplant.
Secondary outcome [12] 419905 0
Change in blood pressure measurements in millimetres of mercury using a sphygmomanometer.
Timepoint [12] 419905 0
At enrolment and at weeks 1, 2, 3, 4, 5, 6, and at 3, 6, 9 and 12 months post liver transplant.
Secondary outcome [13] 419906 0
Change in body weight measurements in kilograms using digital scales.
Timepoint [13] 419906 0
At enrolment, at week 6, and at 3, 6, 9, 12 months post liver transplant.
Secondary outcome [14] 419907 0
Change in waist circumference in centimetres using non-elastic tape measure
Timepoint [14] 419907 0
At enrolment, at week 6, and at 3, 6, 9, 12 months post liver transplant.
Secondary outcome [15] 419908 0
Change in muscle strength as measured with hand grip strength using a calibrated handgrip dynamometer.
Timepoint [15] 419908 0
At enrolment, at week 6, and at 3, 6, 9, 12 months post liver transplant.
Secondary outcome [16] 419909 0
Change in physical frailty measured with the Liver Frailty Index, which is a composite measurement of 3 performance-based tests (dominant hand-grip strength using a calibrated handgrip dynamometer, time to do 5 chair stands in seconds using a stopwatch, seconds holding 3 positions of balance whilst standing using a stopwatch: side, semi-tandem, tandem).
Timepoint [16] 419909 0
At enrolment, at week 6, and at 3, 6, 9, 12 months post liver transplant.
Secondary outcome [17] 419910 0
Change in early morning cortisol levels obtained from a blood test
Timepoint [17] 419910 0
At enrolment, at weeks 1, 2, 4, 6 and at 3, 6, 9, 12 months post liver transplant.
Secondary outcome [18] 419911 0
Change in early morning adrenocorticotropic hormone (ACTH) levels obtained from a blood test
Timepoint [18] 419911 0
At enrolment, at weeks 1, 2, 4, 6 and at 3, 6, 9, 12 months post liver transplant.
Secondary outcome [19] 419912 0
Change in quality of life scores from the Short Form 36 questionnaire.
Timepoint [19] 419912 0
At enrolment, at week 6 and at 6 and 12 months post liver transplant.
Secondary outcome [20] 419913 0
Change in depression scores from the Beck Depression Inventory questionnaire.
Timepoint [20] 419913 0
At enrolment, at week 6 and at 6 and 12 months post liver transplant.
Secondary outcome [21] 419914 0
Total length of stay post liver transplantation in days as documented in electronic medical records.
Timepoint [21] 419914 0
Number of days following liver transplantation.
Secondary outcome [22] 419915 0
Number of hospital re-admissions post liver transplantation as documented in electronic medical records.
Timepoint [22] 419915 0
At 6 and 12 months post liver transplantation.
Secondary outcome [23] 434145 0
Rate of vascular complications (hepatic artery thrombosis, portal vein thrombosis) as documented in the patient's medical record.
Timepoint [23] 434145 0
Secondary outcome [24] 434146 0
Rate of vascular complications (hepatic artery thrombosis, portal vein thrombosis) as documented in the patient's medical record.
Timepoint [24] 434146 0
At weeks 1, 2, 3, 4, 5, 6, and at 3, 6, 9 and 12 months post liver transplant.

Eligibility
Key inclusion criteria
All adult (age 18 years or over) patients accepted for liver transplantation at Austin Health.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Strong medical rationale for a corticosteroid-free protocol (e.g. severe psychiatric comorbidities, high risk of infection) as determined by the Liver Transplant Multidisciplinary Team

- Patient with autoimmune hepatitis

- Corticosteroid dependency prior to trial enrolment

- Patients receiving multi-visceral organ transplantation

- Previous liver transplant recipient requiring redo liver transplant

- Portosystemic shunt >15mm in diameter on imaging which will reduce budesonide first pass metabolism

- Concurrent use of medications that are significant cytochrome P450 3A4 inhibitors (e.g. erythromycin, clarithromycin, verapamil, diltiazem) which will reduce budesonide first pass metabolism

- Unable to take medications enterally (either orally or through tube feeding) by day 3 post liver transplant

- Patients unable to understand written English sufficiently to read PICF or have no carer to assist them with adequate understanding of PICF

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)
A randomisation list will be generated by a Clinical Trials pharmacist, who will then inform study investigators of participant allocation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Patients will be initially stratified based on renal function: either normal renal function or impaired renal function (defined as creatinine >120mg/dL or terlipressin use for hepatorenal syndrome). Once stratified based on renal function, patients will then be randomised 1:1 to either the Control Arm or Budesonide Arm. Block randomisation method will be used.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
17/04/2023
Actual
14/08/2023
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
100
Accrual to date
27
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 24319 0
Austin Health - Austin Hospital - Heidelberg
Recruitment postcode(s) [1] 39878 0
3084 - Heidelberg

Funding & Sponsors
Funding source category [1] 313466 0
Charities/Societies/Foundations
Name [1] 313466 0
Austin Health Medical Research Foundation
Country [1] 313466 0
Australia
Primary sponsor type
Hospital
Name
Austin Health
Address
145 Studley Road, Heidelberg, Victoria, 3084, Australia.
Country
Australia
Secondary sponsor category [1] 315237 0
None
Name [1] 315237 0
Address [1] 315237 0
Country [1] 315237 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312662 0
Austin Health Office for Research
Ethics committee address [1] 312662 0
145 Studley Road, Heidelberg, Victoria, 3084, Australia.
Ethics committee country [1] 312662 0
Australia
Date submitted for ethics approval [1] 312662 0
27/02/2023
Approval date [1] 312662 0
15/06/2023
Ethics approval number [1] 312662 0
Ethics committee name [2] 315138 0
Austin Health Human Research Ethics Committee
Ethics committee address [2] 315138 0
https://www.austin.org.au/Office-for-Research/
Ethics committee country [2] 315138 0
Australia
Date submitted for ethics approval [2] 315138 0
27/02/2023
Approval date [2] 315138 0
15/06/2023
Ethics approval number [2] 315138 0
94771

Summary
Brief summary
This study will investigate whether a drug called budesonide is tolerable and as effective as the standard drug prednisolone in reducing the immune system to prevent organ rejection following liver transplantation. Enrolled participants will be randomly placed into two groups. In the control group, participants will be given standard immunosuppression with prednisolone following their liver transplant. In the intervention group, participants will be given budesonide instead of prednisolone. We will compare rates of organ rejection and differences in infectious, metabolic, musculoskeletal, endocrine and psychological complications between the two groups. We predict budesonide will be comparable to prednisolone in preventing organ rejection following liver transplantation, whilst resulting in fewer side effects.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 125470 0
A/Prof Marie Sinclair
Address 125470 0
Austin Health
145 Studley Road, Heidelberg
Victoria, 3084
Australia.
Country 125470 0
Australia
Phone 125470 0
+61412733736
Fax 125470 0
Email 125470 0
marie.sinclair@austin.org.au
Contact person for public queries
Name 125471 0
Dr Dorothy Liu
Address 125471 0
Austin Health
145 Studley Road, Heidelberg
Victoria, 3084
Australia.
Country 125471 0
Australia
Phone 125471 0
+61 03 9496 5353
Fax 125471 0
Email 125471 0
dorothy.liu2@austin.org.au
Contact person for scientific queries
Name 125472 0
Dr Dorothy Liu
Address 125472 0
Austin Health
145 Studley Road, Heidelberg
Victoria, 3084
Australia.
Country 125472 0
Australia
Phone 125472 0
+61 03 9496 5353
Fax 125472 0
Email 125472 0
dorothy.liu2@austin.org.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 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.