None listed
Conditions
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.
Interventions
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.
Sponsors
Austin Health
Study design
Allocation
Randomised controlled trial
Intervention model
Parallel
Primary purpose
Treatment
Masking
Blinded (masking used) (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
Male
Age
18 Years to 75 Years
Healthy volunteers
No
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 (less than or equal to 40 Houndsfield units) c. Controlled attenuation parameter on fibroscan above 270dB/m 2) Age 18 to 75 years of age. 3) Plasma total testosterone less than or equal to 12nmol/L or free testosterone less than or equal to 230pmol/L on two occasions. 4) Fibroscan greater than or equal to 7.0kPa OR ALT greater than or equal to 30u/L, to identify men at risk of progression of liver disease.
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)
Outcome results
None listed