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Trial registered on ANZCTR


Registration number
ACTRN12619000701123p
Ethics application status
Not yet submitted
Date submitted
5/05/2019
Date registered
9/05/2019
Date last updated
9/05/2019
Date data sharing statement initially provided
9/05/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Testosterone therapy for the treatment of non alcoholic fatty liver disease
Scientific title
Testosterone Undecanoate for the treatment of non alcoholic fatty liver disease (TNT) trial
Secondary ID [1] 298093 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Non-alcoholic fatty liver disease 312603 0
Testosterone deficiency 312604 0
Condition category
Condition code
Oral and Gastrointestinal 311112 311112 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients will receive either 1000mg of testosterone undecanoate in a 4mL oily solution or a matching oil-based placebo of the same volume via intramuscular injection into the gluteal muscle by experienced nursing staff. Drug administration will occur at the baseline visit, 6 weeks, then 3 monthly thereafter as per manufacturer instructions with the last dose delivered at 9 months. Supervised administration of trial drug removes any potential for compliance issues.
Intervention code [1] 314322 0
Treatment: Drugs
Comparator / control treatment
The comparator will be a matching placebo as outlined above.
Control group
Placebo

Outcomes
Primary outcome [1] 319890 0
Percentage change in hepatic steatosis as quantified by magnetic resonance imaging proton fat fraction (MRI-PDFF).
Timepoint [1] 319890 0
12 months
Secondary outcome [1] 369791 0
Change in liver fibrosis estimates by Fibroscan, FIB-4, NAFLD fibrosis score and MRI cT1 by Perspectum Diagnostics Liver MultiScan
Timepoint [1] 369791 0
12 months
Secondary outcome [2] 369792 0
Change in serum ALT
Timepoint [2] 369792 0
12 months
Secondary outcome [3] 369793 0
Change in insulin resistance as measured by the HOMA-IR
Timepoint [3] 369793 0
12 months
Secondary outcome [4] 369795 0
Change in body composition as measured by a composite of lean mass, fat mass and visceral fat by dual energy x-ray absorptiometry
Timepoint [4] 369795 0
12 months
Secondary outcome [5] 369796 0
Change in muscle strength as measured by Handgrip strength
Timepoint [5] 369796 0
12 months
Secondary outcome [6] 369798 0
Change in health-related quality of life as measured by the short form-36 questionnaire (SF36)
Timepoint [6] 369798 0
12 months
Secondary outcome [7] 369799 0
Change in serum total cholesterol level
Timepoint [7] 369799 0
12 months
Secondary outcome [8] 369800 0
Change in body mass index (in meters per kilogram squared) as measured using a stadiometer and digital scales
Timepoint [8] 369800 0
12 months
Secondary outcome [9] 370104 0
Change in fasting blood glucose level
Timepoint [9] 370104 0
12 months
Secondary outcome [10] 370105 0
Change in HbA1c level as measured in mmol/mol by serum assay
Timepoint [10] 370105 0
12 months
Secondary outcome [11] 370106 0
Change in health-related quality of life as measured by the Androgen Deficiency in the Ageing Male (ADAM) questionnaire
Timepoint [11] 370106 0
12 months
Secondary outcome [12] 370107 0
Change in serum LDL level
Timepoint [12] 370107 0
12 months
Secondary outcome [13] 370108 0
Change in serum HDL level
Timepoint [13] 370108 0
12 months
Secondary outcome [14] 370109 0
Change in serum triglyceride level
Timepoint [14] 370109 0
12 months
Secondary outcome [15] 370110 0
Change in waist circumference (cm)
Timepoint [15] 370110 0
12 months

Eligibility
Key inclusion criteria
1) Men with estimated hepatic steatosis greater than or equal to 30% by meeting =1 of the following criteria:
a. Diffuse increased echogenicity of the liver parenchyma on ultrasound as compared to echogenicity of renal cortex or spleen
b. Reduced attenuation on CT scan (<40 Houndsfield units)
c. Controlled attenuation parameter on fibroscan above 270dB/m
2) Age 18 to 75 years of age.
3) Plasma total testosterone <12nmol/L or free testosterone <230pmol/L on two occasions.
4) Fibroscan >7.0kPa OR ALT >30u/L, to identify men at risk of progression of liver disease.
Minimum age
18 Years
Maximum age
75 Years
Gender
Males
Can healthy volunteers participate?
No
Key exclusion criteria
1) Alcohol consumption >21 units per week >2 weeks in the last year or >3 months of the past 5 years to exclude inadvertent inclusion of patients with alcoholic liver disease
2) Other significant cause for liver disease, including autoimmune liver disease, metabolic liver disease such as Wilson’s disease or hereditary haemachromatosis, or viral hepatitis (excluding Hepatitis C virus treated >12 months ago)
3) Prostate cancer, elevated PSA or abnormal prostate on digital rectal exam
4) Hepatocellular or other active cancer
5) Current or previous (within 12 months) testosterone or androgen deprivation therapy
6) Severe renal impairment (eGFR <30ml/min)
7) Symptomatic ischaemic heart disease or significant heart failure symptoms (New York Heart Association class III or IV)
8) Uncontrolled hypertension >160/100mHg
9) Uncontrolled obstructive sleep apnoea
10) Decompensated cirrhosis, as evidence by Child Pugh Score B or C, given risk of death or transplantation within the study period
11) Contraindications to MRI (non-MRI-compatible pacemaker or other device, severe claustrophobia, inability to breath hold)

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)
Allocation concealment via central randomisation by computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Subjects will be assigned to groups by simple randomisation using computer software with equal probability in blocks of 4 by the presence or absence of insulin use (due to its potential impact on liver fat and reflection of severity of diabetes) by clinical trials pharmacists not involved in study design.
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
Type of endpoint(s)
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Not yet 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] 13685 0
Austin Health - Austin Hospital - Heidelberg
Recruitment postcode(s) [1] 26375 0
3084 - Heidelberg

Funding & Sponsors
Funding source category [1] 302624 0
Self funded/Unfunded
Name [1] 302624 0
No funding at present, applying for NHMRC grant
Address [1] 302624 0
-
Country [1] 302624 0
Primary sponsor type
Hospital
Name
Austin Health
Address
145 Studley Road, Heidelberg, VIC, 3084
Country
Australia
Secondary sponsor category [1] 302534 0
None
Name [1] 302534 0
Address [1] 302534 0
Country [1] 302534 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 303254 0
Austin Health Human Research Ethics Committee
Ethics committee address [1] 303254 0
145 Studley Road, Heidelberg, VIC, 3084
Ethics committee country [1] 303254 0
Australia
Date submitted for ethics approval [1] 303254 0
01/11/2019
Approval date [1] 303254 0
Ethics approval number [1] 303254 0

Summary
Brief summary
Non-alcoholic fatty liver disease (NAFLD) is rapidly rising in prevalence worldwide and is responsible for growing numbers of cases of hepatocellular carcinoma and end-stage liver disease. There is currently no PBS-listed therapy for NAFLD in Australia. Low testosterone (T) is common in men with NAFLD and may contribute to disease prevalence and severity by increasing visceral fat, insulin resistance and altering hepatic metabolism. The impact of T therapy in men with NAFLD and low T levels remains unknown, but it is biological plausible that T will reduce hepatic fat content both via direct actions on hepatic sex steroid receptor signalling as well as indirectly, via promoting metabolically favourable changes in body composition and whole body glucose metabolism.

Our aim is to conduct a randomized, placebo-controlled trial of intramuscular T therapy for 12 months in 120 men with NAFLD and low T levels to investigate its impact on hepatic steatosis. Our hypothesis is that T therapy will reduce hepatic steatosis and our primary endpoint is a 15% relative reduction in hepatic steatosis as measured by MRI fat fraction. Our secondary hypotheses are that T therapy will lead to improved liver enzymes, reduced insulin resistance, reduced visceral fat, increased lean mass and muscle strength and a reduction in liver fibrosis, as measured by MRI, Fibroscan and non-invasive blood markers.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 93026 0
Dr Marie Sinclar
Address 93026 0
Austin Health, 145 Studley Road, Heidelberg, VIC, 3084
Country 93026 0
Australia
Phone 93026 0
+61 3 94965353
Fax 93026 0
Email 93026 0
marie.sinclair@austin.org.au
Contact person for public queries
Name 93027 0
Dr Marie Sinclar
Address 93027 0
Austin Health, 145 Studley Road, Heidelberg, VIC, 3084
Country 93027 0
Australia
Phone 93027 0
+61 3 94965353
Fax 93027 0
Email 93027 0
marie.sinclair@austin.org.au
Contact person for scientific queries
Name 93028 0
Dr Marie Sinclar
Address 93028 0
Austin Health, 145 Studley Road, Heidelberg, VIC, 3084
Country 93028 0
Australia
Phone 93028 0
+61 3 94965353
Fax 93028 0
Email 93028 0
marie.sinclair@austin.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All de-identified patient data collected during the trial
When will data be available (start and end dates)?
Following publication, no end date
Available to whom?
Case-by-case at the discretion of the Principal Investigator
Available for what types of analyses?
Any purpose
How or where can data be obtained?
Subject to approval by Principal Investigator
What supporting documents are/will be available?
Study protocol
Statistical analysis plan
Informed consent form
Clinical study report
Ethical approval
Summary results
No Results