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Trial registered on ANZCTR


Registration number
ACTRN12618000802202
Ethics application status
Approved
Date submitted
3/05/2018
Date registered
11/05/2018
Date last updated
2/05/2019
Date data sharing statement initially provided
2/05/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
The Impact of Branched Chain Amino Acids (BCAA) Supplementation in Patients with Advanced Liver Disease
Scientific title
The impact of Branched-Chain Amino Acid supplementation on sarcopenia, insulin resistance and immune function in patients with advanced liver disease
Secondary ID [1] 294209 0
-Nil known
Universal Trial Number (UTN)
U1111-1213-3605
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cirrhosis
306853 0
Sarcopenia 306854 0
Malnutrition 306855 0
Hepatic encephalopathy 306856 0
Infections 306857 0
Insulin resistance 306858 0
Immune function 306859 0
Condition category
Condition code
Oral and Gastrointestinal 305947 305947 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
Diet and Nutrition 305948 305948 0 0
Other diet and nutrition disorders
Infection 305950 305950 0 0
Studies of infection and infectious agents
Inflammatory and Immune System 305951 305951 0 0
Other inflammatory or immune system disorders
Metabolic and Endocrine 305952 305952 0 0
Diabetes
Musculoskeletal 305953 305953 0 0
Other muscular and skeletal disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients with cirrhosis, muscle weakness as defined by handgrip dynamometer and evidence of low serum albumin or ascites will be invited to participate in the study. 150 patients will be recruited and randomised to the intervention arm and a control arm. The intervention arm will be blinded to receive powdered BCAA supplements. These contain leucine, isoleucine and valine in a 2:1:1 ratio respectively. Patients in the intervention arm will be given powdered BCAA supplements and will be asked to take 30g orally per day mixed with water, milk or juice. The duration of intervention will be 12 months. Compliance will be monitored through return and weighing of supplement packages at each clinical review.
Intervention code [1] 300499 0
Treatment: Drugs
Comparator / control treatment
Patients randomised to the control arm will be given a whey protein isolate powder with equal protein content to BCAA supplement. They will be asked to take 30g orally per day for 12 months.
Control group
Active

Outcomes
Primary outcome [1] 304996 0
Upper limb muscle mass as measured by Dual energy X-ray Absorptiometry (DEXA)
Timepoint [1] 304996 0
Upper limb muscle mass will be assessed at baseline, 6 months and 12 months [primary timepoint] of intervention.
Primary outcome [2] 305763 0
Changes in handgrip strength as measured by handgrip dynamometry
Timepoint [2] 305763 0
Handgrip strength will be assessed at baseline, 1 month, 3 months, 6 months, 9 months and 12 months [primary timepoint] of intervention.
Secondary outcome [1] 343827 0
Changes in muscle mass as defined by an increase in skeletal muscle index calculated via on single Slice CT scan at 3rd Lumbar vertebrae
Timepoint [1] 343827 0
Assessment at baseline and 12 months of treatment
Secondary outcome [2] 343830 0
Changes in functional measures of sarcopenia including Fried Frailty Index and Short Physical Performance Battery
Timepoint [2] 343830 0
Assessed at baseline, 3, 6, 9 and 12 months of treatment
Secondary outcome [3] 343831 0
Change in serum biochemistry (liver function tests, albumin)
Timepoint [3] 343831 0
Measures to be taken at 0, 1, 3, 6, 9 and 12 months of intervention
Secondary outcome [4] 343832 0
Insulin resistance as measured by HbA1C, HOMA-IR and HOMA-%B scores calculated using fasting insulin and glucose recordings.
Timepoint [4] 343832 0
Assessed at 0, 1, 3, 6 and 12 months of treatment
Secondary outcome [5] 343833 0
Immune function as measured by QUANTIFERON-Monitor assay
Timepoint [5] 343833 0
Assessed at 0, 1, 3, 6, 9 and 12 months of treatment
Secondary outcome [6] 343834 0
Quality of life measures as assess using the chronic liver disease questionnaire (CLDQ)
Timepoint [6] 343834 0
Assessed at 0, 3, 6, 9 and 12 months of treatment
Secondary outcome [7] 346518 0
Anthropometry: triceps skinfold measured by skinfold calipers, and mid-upper arm circumference measured with tape measure
Timepoint [7] 346518 0
Measured at baseline, 3 months, 6 months, 9 months and 12 months of treatment
Secondary outcome [8] 346519 0
Metabolic rate measured by an indirect calorimeter
Timepoint [8] 346519 0
measured at 0, 3, 6 and 12 months of treatment
Secondary outcome [9] 346520 0
Rates of hepatic encephalopathy measured using the trail making test and Stroop Test
Timepoint [9] 346520 0
Measured at 0, 3, 6 and 12 months of treatment
Secondary outcome [10] 346642 0
Rates of hospitalisation
Outcome measured via data linkage to medical records.
Timepoint [10] 346642 0
As measured in days over 12 months of intervention
Secondary outcome [11] 346698 0
Rates of clinical significant infections.
Outcome measured via data linkage to medical records.
Timepoint [11] 346698 0
Measured in episodes over 12 months of intervention.
Secondary outcome [12] 346742 0
Direct healthcare costs
Outcome measured by admissions to hospital via data linkage to medical records
Timepoint [12] 346742 0
Measured at 12 months of intervention

Eligibility
Key inclusion criteria
Adult patients who meet the following criteria will be invited to participate
1. Cirrhosis with a radiological, clinical or histological diagnosis
2. A low serum albumin or the presence of ascites
3. Muscle weakness as determined by hand dynamometer
Minimum age
18 Years
Maximum age
75 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Patients > 75 and < 18 years of age
- Prognosis or time to transplant < 6 months as determined by the treating clinician
- Active heavy alcohol intake
- Advanced hepatocellular carcinoma
- Lactose intolerance

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)
Randomisation will occur independently through the pharmacy department. Patients will be administered the intervention or standard of care supplement powder in unlabelled packaging. The investigator and participant will be blinded to intervention group.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Statistical methods / analysis
To detect a difference at 12 months between the intervention and control group using the composite endpoints of a difference of 5% in upper limb appendicular muscle mass on DEXA and / or 5% increase in handgrip strenght, with a p-value set at 0.05 and a power of 80%, we estimate that each group will need 67 subjects. We estimate a drop-out rate of up to 10%, therefore we aim to recruit 150 patients.

Outcomes will be analysed on an intention to treat analysis. While most subjects will reach at least 6 months in the study some may drop because of transplantation or death. Those who achieve between 6 and 12 months follow up will be included in the intention to treat analysis provided a DEXA is completed allowing for documentation of APLM. If anything, this will skew results to the null hypothesis as less of a change in APLM is expected at only 6 months follow up compared to the intended duration of 12 months. Therefore, if anything, dropouts may lead to an under-estimation of treatment effect and minimize the risk of identifying a false positive result.

Recruitment
Recruitment status
Recruiting
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] 10834 0
Austin Health - Austin Hospital - Heidelberg
Recruitment postcode(s) [1] 22579 0
3084 - Heidelberg

Funding & Sponsors
Funding source category [1] 298846 0
Charities/Societies/Foundations
Name [1] 298846 0
Austin Medical Research Foundation
Address [1] 298846 0
145 Studley Rd,
Heidelberg, VIC, 3084
Country [1] 298846 0
Australia
Primary sponsor type
Hospital
Name
Austin Health
Address
145 Studley Rd,
Heidelberg, VIC, 3084
Country
Australia
Secondary sponsor category [1] 298681 0
None
Name [1] 298681 0
Address [1] 298681 0
Country [1] 298681 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299790 0
Austin Health Human Research Ethics Committee
Ethics committee address [1] 299790 0
145 Studley Road
Heidelberg VIC 3084
Ethics committee country [1] 299790 0
Australia
Date submitted for ethics approval [1] 299790 0
22/11/2017
Approval date [1] 299790 0
14/05/2018
Ethics approval number [1] 299790 0

Summary
Brief summary
Advanced liver disease, or cirrhosis, is associated with increased morbidity and mortality and patients suffer frequent complications. Sarcopenia, defined as the the loss of muscle mass as well as muscle function, is among the commonest complications, with an estimated prevalence of up to 70%. Sarcopenia is independently associated with reduced survival, increased infection risk and higher rates of hospitalisation in this cohort. Despite this, little is known about how to increase muscle mass in this population.

Branched chain amino acids (BCAAs) include three essential amino acids which are used as building blocks for protein and energy in muscle. In addition to being the primary energy source for skeletal muscle, they are also used to help clear toxins that build up in liver disease. Patients with cirrhosis have reduced levels of BCAAs, which is thought to be a major contributing factor that contributes to low muscle mass in these patients.

Treating patients with oral BCAA supplements, in the form of a soluble powder, may improve quality of life and overall nutrition in patients with cirrhosis. However, the impact on muscle mass is unknown. Our study aims to investigate the effect of oral BCAA powdered supplements on sarcopenia in patients with cirrhosis. Our randomised trial will compare BCAAs to a control protein supplement to assess whether replacing dietary protein deficit as a whole or BCAAs specifically can influence outcomes. Our primary outcome will be an increase in muscle mass and strength in treated subjects. If we can improve sarcopenia, we anticipate we may also improve other outcomes. Therefore, our secondary outcomes of this study will be improved muscle function, hepatic encephalopathy, insulin resistance, rates of hospitalisation, health care costs, quality of life and overall mortality. Given the higher rates of infections seen in patients with sarcopenia, the second focus of our study will be on immune function through monitoring blood samples and infectious complications.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 81574 0
A/Prof Paul Gow
Address 81574 0
Austin Health
145 Studley Rd
Heidelberg, VIC, 3084
Country 81574 0
Australia
Phone 81574 0
+61 3 9496 5353
Fax 81574 0
Email 81574 0
paul.gow@austin.org.au
Contact person for public queries
Name 81575 0
Dr Penelope Hey
Address 81575 0
Austin Health
145 Studley Rd
Heidelberg, VIC, 3084
Country 81575 0
Australia
Phone 81575 0
+61 3 9496 5353
Fax 81575 0
Email 81575 0
penelope.hey@austin.org.au
Contact person for scientific queries
Name 81576 0
Dr Penelope Hey
Address 81576 0
Austin Health
145 Studley Rd
Heidelberg, VIC, 3084
Country 81576 0
Australia
Phone 81576 0
+61 3 9496 5353
Fax 81576 0
Email 81576 0
penelope.hey@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 other documents available
Summary results
No Results