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Trial registered on ANZCTR
Registration number
ACTRN12616000756426p
Ethics application status
Not yet submitted
Date submitted
3/06/2016
Date registered
9/06/2016
Date last updated
9/06/2016
Type of registration
Prospectively registered
Titles & IDs
Public title
Testosterone treatment in men with liver disease
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Scientific title
Effect of Testosterone Treatment on Mortality and Hospitalisation in Men with Liver Cirrhosis and low serum testosterone: A Randomized Controlled Trial
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Secondary ID [1]
289358
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nil known
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Universal Trial Number (UTN)
U1111-1183-8042
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
cirrhosis
298990
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hypogonadism
298991
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Condition category
Condition code
Oral and Gastrointestinal
299054
299054
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0
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Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
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Metabolic and Endocrine
299055
299055
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0
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Other endocrine disorders
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Intramuscular testosterone undecanoate (1000mg in 4mL) administered according to manufacturer instructions (0 weeks, 6 weeks, then 12 weekly thereafter) for 24 months
All doses will be administered on-site by nursing staff and logged by trial staff
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Intervention code [1]
294942
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Treatment: Drugs
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Comparator / control treatment
Intramuscular injection of an identical oil-based solution, but without the active ingredient, also 4mL volume
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Control group
Placebo
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Outcomes
Primary outcome [1]
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Difference in the rate of the composite endpoint of either mortality and/or major infection requiring hospitalisation in T treated subjects as compared to placebo subjects
-infection will be diagnosed according to NACSELD criteria (North American Consortium for Studies of End-stage Liver Disease)
-mortality and hospital admission identified on review of hospital records, and communication with other hospitals / medical practitioners where required
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Assessment method [1]
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Timepoint [1]
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2 years
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Secondary outcome [1]
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mortality
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Assessment method [1]
324459
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Timepoint [1]
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2 years
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Secondary outcome [2]
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Liver transplantation
-review of medical records
-all transplants performed in the study centres and thus simple to capture through internal records
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Assessment method [2]
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Timepoint [2]
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2 years
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Secondary outcome [3]
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Total number of days in hospital
-assessed by review of medical records, both in the home institution and elsewhere, with communication with other facilities where required (with patient consent)
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Assessment method [3]
324461
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Timepoint [3]
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2 years, or until time of dropout
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Secondary outcome [4]
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Body composition by dual energy x-ray absorptiometry (DEXA).
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Assessment method [4]
324465
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Timepoint [4]
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2 years, with measurements conducted 6-monthly
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Secondary outcome [5]
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Handgrip strength by Jamar dynamometer
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Assessment method [5]
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Timepoint [5]
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2 years, with measurements performed 6 monthly
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Secondary outcome [6]
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Health related quality of life as measured by the Chronic Liver Disease questionnaire
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Assessment method [6]
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Timepoint [6]
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2 years, measurements performed 6 monthly
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Secondary outcome [7]
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Calculated insulin resistance, using:
-fasting serum glucose
-fasting serum insulin
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Assessment method [7]
324468
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Timepoint [7]
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2 years, measurements performed 3 monthly
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Secondary outcome [8]
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Direct health-care costs per month, by data linkage to hospital cost records
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Assessment method [8]
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Timepoint [8]
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2 years, or until time of drop-out
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Secondary outcome [9]
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Physical function
-short physical performance battery test
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Assessment method [9]
324538
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Timepoint [9]
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2 years
-measured 6 monthly
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Secondary outcome [10]
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Physical activity
-accelerometer will be worn for a 2 week period every 6 months
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Assessment method [10]
324539
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Timepoint [10]
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2 years
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Secondary outcome [11]
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Glycaemic control
-HbA1c
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Assessment method [11]
324540
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Timepoint [11]
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2 years, measured every 3 months
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Eligibility
Key inclusion criteria
Men with cirrhosis and low serum testosterone
-cirrhosis defined on clinical grounds, by a combination of clinical, biochemical and radiological features. In equivocal cases, a fibroscan reading of >20kPa is required to avoid the inadvertent inclusion of non-cirrhotics
-low serum testosterone requires 2 x morning blood samples that meet criteria: total T <12nmol/L OR free T <230pmol/L
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Minimum age
40
Years
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Maximum age
70
Years
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Sex
Males
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Can healthy volunteers participate?
No
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Key exclusion criteria
1) Prostate cancer, elevated PSA or abnormal prostate on digital rectal exam
2) Hepatocellular or other active cancer
3) Current or previous (within 12 months) testosterone or androgen deprivation therapy
4) Severe renal impairment (eGFR <30ml/min)
5) Symptomatic ischaemia heart disease or significant heart failure symptoms (New York Heart Association class III or IV)
6) Uncontrolled hypertension >160/100mHg
7) Uncontrolled obstructive sleep apnoea
8) Platelet count <30 x 10^9 given the need for intramuscular drug administration
9) Other non-liver disease thought to lead to death or severe debility within 2 years
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Yes - double blinded, allocation concealed, patients randomised by computer, coordinated by clinical pharmacists not involved in the study administration
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Subjects will be randomised using a computer-generated sequence with equal probability by Child Pugh Class (A, B or C) by clinical trials pharmacists not involved in study design, and stratified by study centre
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Masking / blinding
Blinded (masking used)
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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
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 3 / Phase 4
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Type of endpoint/s
Efficacy
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Statistical methods / analysis
Statistical analysis of treatment effects on primary and secondary endpoints will according to “intention-to-treat” principles. All subjects who receive at least one dose of trial medication will be included in the analysis. We will use an intention-to-treat analysis of all randomised participants with relevant sensitivity analyses. This will use a generalised linear mixed model for longitudinal analysis to estimate both temporal (random, repeat measure) and treatment effects. This model allows adjustment for time x treatment interactions, adjustment for baseline levels and is robust to missing-at-random data. Possible bias by different study centres will be assessed and adjusted for as a fixed effect by centre. The primary endpoint (mean fully adjusted treatment effects with 95% CI) will be the treatment change over time represented by the interaction term in the model. A per-protocol analysis is also planned
The sample size has been calculated to be 250 based on assumptions made from our initial 12 month RCT. In this RCT, infection or death occurred in 32% of subjects on testosterone and 49% of subjects on placebo. The patients that completed the RCT were a healthier group than those who dropped out, with a lower MELD score and higher serum testosterone, thus we expect a lower event rate for the second 12 months. We therefore estimate the event rate for 2 years to be 1.5 times the 12 month event rate, at 48% in testosterone-treated subjects versus 73% on placebo. To demonstrate a 25% reduction in the composite endpoint over 2 years with power of 80% and a type I error rate of 0.05 and type II error rate of 0.2, a sample size of 118 is required. Given the dropout rate in our initial RCT of just over 50%, we aim to recruit 250 men, 125 in each group
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Recruitment
Recruitment status
Not yet recruiting
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Date of first participant enrolment
Anticipated
1/04/2017
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Actual
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Date of last participant enrolment
Anticipated
1/10/2019
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Actual
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Date of last data collection
Anticipated
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Actual
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Sample size
Target
250
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Accrual to date
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Final
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Recruitment in Australia
Recruitment state(s)
NSW,VIC
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Recruitment hospital [1]
5901
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Austin Health - Austin Hospital - Heidelberg
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Recruitment hospital [2]
5902
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Royal Prince Alfred Hospital - Camperdown
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Recruitment postcode(s) [1]
13345
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3084 - Heidelberg
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Recruitment postcode(s) [2]
13346
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2050 - Camperdown
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Funding & Sponsors
Funding source category [1]
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Self funded/Unfunded
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Name [1]
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currently seeking funding
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Address [1]
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currently seeking funding
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Country [1]
293741
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Primary sponsor type
Hospital
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Name
Austin Hospital
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Address
Liver Transplant Unit
145 Studley Road
Heidelberg
Victoria
3084
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Country
Australia
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Secondary sponsor category [1]
292570
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Hospital
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Name [1]
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Royal Prince Alfred Hospital
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Address [1]
292570
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11, KGV Building, Missenden Rd
Camperdown, Sydney
2050
NSW
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Country [1]
292570
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Australia
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Other collaborator category [1]
279017
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University
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Name [1]
279017
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The University of Melbourne
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Address [1]
279017
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Grattan St
Parkville
Victoria
3050
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Country [1]
279017
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Australia
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Ethics approval
Ethics application status
Not yet submitted
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Ethics committee name [1]
295178
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Austin Health Human Research Ethics Committee
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Ethics committee address [1]
295178
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Office for Research,
Austin Life Sciences
Austin Health
PO Box 5555
Heidelberg
Victoria
Australia, 3084
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Ethics committee country [1]
295178
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Australia
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Date submitted for ethics approval [1]
295178
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30/09/2016
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Approval date [1]
295178
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Ethics approval number [1]
295178
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Summary
Brief summary
Many cirrhotic men have reduced testosterone (T) levels. We recently found that testosterone deficiency is an independent predictor of death in this population. One possible explanation for this is that testosterone deficiency contributes to sarcopenia, a known risk factor for the development of both serious infections and mortality in cirrhotics. In a recent 12 month randomised study we showed that testosterone treatment has multiple short term beneficial effects in testosterone deficient cirrhotic men. These included improvement of sarcopenia, increased bone mass and increased haematocrit. However, this study was not powered to assess the effects of testosterone treatment on the major clinical endpoints linked to sarcopenia in cirrhosis of infection and death.
We therefore propose to conduct a multi-centre randomised placebo-controlled trial (RCT) of 24 months T treatment in 250 cirrhotic men with a low T level (serum total T < 12nmol/L or free T < 230pmol/L) to investigate whether T treatment will reduce the composite outcome of mortality or hospitalisation for infection.
Primary hypothesis: In cirrhotic men with low testosterone, T therapy will reduce the composite outcome of mortality or hospitalisation for infection, a major trigger for decompensation in chronic liver disease
Secondary hypotheses: T treatment will improve the following measures: total numbers of days in hospital, muscle mass, muscle function, bone mass, fat mass, insulin resistance, haemoglobin and quality of life
Aim: To conduct a 2-year, multi-centre, randomised, double-blinded, placebo-controlled trial to determine if T treatment together with dietary and exercise advice improves outcomes in men with cirrhosis.
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Trial website
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Prof Peter W Angus
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Address
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Victorian Liver Transplant Unit
Austin Health
145 Studley Road
Heidelberg, Vic
3084
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Country
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Australia
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Phone
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+613 9496 5353
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Fax
66390
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+613 9496 3487
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Email
66390
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[email protected]
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Contact person for public queries
Name
66391
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Dr Marie Sinclair
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Address
66391
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Victorian Liver Transplant Unit
Austin Health
145 Studley Road
Heidelberg, Vic
3084
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Country
66391
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Australia
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Phone
66391
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+613 9496 5353
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Fax
66391
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+613 9496 3487
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Email
66391
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[email protected]
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Contact person for scientific queries
Name
66392
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Dr Marie Sinclair
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Address
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Victorian Liver Transplant Unit
Austin Health
145 Studley Road
Heidelberg, Vic
3084
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Country
66392
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Australia
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Phone
66392
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+613 9496 5353
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Fax
66392
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+613 9496 3487
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Email
66392
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[email protected]
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No information has been provided regarding IPD availability
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.
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