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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
Scientific title
Effect of Testosterone Treatment on Mortality and Hospitalisation in Men with Liver Cirrhosis and low serum testosterone: A Randomized Controlled Trial
Secondary ID [1] 289358 0
nil known
Universal Trial Number (UTN)
U1111-1183-8042
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
cirrhosis 298990 0
hypogonadism 298991 0
Condition category
Condition code
Oral and Gastrointestinal 299054 299054 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
Metabolic and Endocrine 299055 299055 0 0
Other endocrine disorders

Intervention/exposure
Study type
Interventional
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
Intervention code [1] 294942 0
Treatment: Drugs
Comparator / control treatment
Intramuscular injection of an identical oil-based solution, but without the active ingredient, also 4mL volume
Control group
Placebo

Outcomes
Primary outcome [1] 298526 0
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
Timepoint [1] 298526 0
2 years
Secondary outcome [1] 324459 0
mortality
Timepoint [1] 324459 0
2 years
Secondary outcome [2] 324460 0
Liver transplantation
-review of medical records
-all transplants performed in the study centres and thus simple to capture through internal records
Timepoint [2] 324460 0
2 years
Secondary outcome [3] 324461 0
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)
Timepoint [3] 324461 0
2 years, or until time of dropout
Secondary outcome [4] 324465 0
Body composition by dual energy x-ray absorptiometry (DEXA).
Timepoint [4] 324465 0
2 years, with measurements conducted 6-monthly
Secondary outcome [5] 324466 0
Handgrip strength by Jamar dynamometer
Timepoint [5] 324466 0
2 years, with measurements performed 6 monthly
Secondary outcome [6] 324467 0
Health related quality of life as measured by the Chronic Liver Disease questionnaire
Timepoint [6] 324467 0
2 years, measurements performed 6 monthly
Secondary outcome [7] 324468 0
Calculated insulin resistance, using:
-fasting serum glucose
-fasting serum insulin
Timepoint [7] 324468 0
2 years, measurements performed 3 monthly
Secondary outcome [8] 324469 0
Direct health-care costs per month, by data linkage to hospital cost records
Timepoint [8] 324469 0
2 years, or until time of drop-out
Secondary outcome [9] 324538 0
Physical function
-short physical performance battery test
Timepoint [9] 324538 0
2 years
-measured 6 monthly
Secondary outcome [10] 324539 0
Physical activity
-accelerometer will be worn for a 2 week period every 6 months
Timepoint [10] 324539 0
2 years
Secondary outcome [11] 324540 0
Glycaemic control
-HbA1c
Timepoint [11] 324540 0
2 years, measured every 3 months

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
Minimum age
40 Years
Maximum age
70 Years
Sex
Males
Can healthy volunteers participate?
No
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

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)
Yes - double blinded, allocation concealed, patients randomised by computer, coordinated by clinical pharmacists not involved in the study administration
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
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 3 / Phase 4
Type of endpoint/s
Efficacy
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

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/04/2017
Actual
Date of last participant enrolment
Anticipated
1/10/2019
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
250
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 5901 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [2] 5902 0
Royal Prince Alfred Hospital - Camperdown
Recruitment postcode(s) [1] 13345 0
3084 - Heidelberg
Recruitment postcode(s) [2] 13346 0
2050 - Camperdown

Funding & Sponsors
Funding source category [1] 293741 0
Self funded/Unfunded
Name [1] 293741 0
currently seeking funding
Country [1] 293741 0
Primary sponsor type
Hospital
Name
Austin Hospital
Address
Liver Transplant Unit
145 Studley Road
Heidelberg
Victoria
3084
Country
Australia
Secondary sponsor category [1] 292570 0
Hospital
Name [1] 292570 0
Royal Prince Alfred Hospital
Address [1] 292570 0
11, KGV Building, Missenden Rd
Camperdown, Sydney
2050
NSW
Country [1] 292570 0
Australia
Other collaborator category [1] 279017 0
University
Name [1] 279017 0
The University of Melbourne
Address [1] 279017 0
Grattan St
Parkville
Victoria
3050
Country [1] 279017 0
Australia

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 295178 0
Austin Health Human Research Ethics Committee
Ethics committee address [1] 295178 0
Office for Research,
Austin Life Sciences
Austin Health
PO Box 5555
Heidelberg
Victoria
Australia, 3084
Ethics committee country [1] 295178 0
Australia
Date submitted for ethics approval [1] 295178 0
30/09/2016
Approval date [1] 295178 0
Ethics approval number [1] 295178 0

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.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 66390 0
Prof Peter W Angus
Address 66390 0
Victorian Liver Transplant Unit
Austin Health
145 Studley Road
Heidelberg, Vic
3084
Country 66390 0
Australia
Phone 66390 0
+613 9496 5353
Fax 66390 0
+613 9496 3487
Email 66390 0
[email protected]
Contact person for public queries
Name 66391 0
Marie Sinclair
Address 66391 0
Victorian Liver Transplant Unit
Austin Health
145 Studley Road
Heidelberg, Vic
3084
Country 66391 0
Australia
Phone 66391 0
+613 9496 5353
Fax 66391 0
+613 9496 3487
Email 66391 0
[email protected]
Contact person for scientific queries
Name 66392 0
Marie Sinclair
Address 66392 0
Victorian Liver Transplant Unit
Austin Health
145 Studley Road
Heidelberg, Vic
3084
Country 66392 0
Australia
Phone 66392 0
+613 9496 5353
Fax 66392 0
+613 9496 3487
Email 66392 0
[email protected]

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