Bicalutamide Therapy in Young Women With NAFLD and PCOS

This is a single center, double-blind, placebo-controlled, randomized, (1:1) parallel group pilot clinical trial of bicalutamide in women with either biopsy-proven or believed NAFLD receiving 6 months of bicalutamide or placebo. 50 women are targeted for enrollment. Each participant will be administered a single dose of bicalutamide or placebo once daily for a total of 6 months. In person evaluations will take place at Month 1, 2, 3, 4, 5, and 6. There will be a telephone follow up visit within 1 month of end of treatment. This is a pilot clinical trial that is largely feasibility focused. Study outcomes will include:

• Change in liver stiffness on Magnetic Resonance Elastography (MRE)
• Change in hepatic steatosis by Magnetic Resonance Proton Density Fat Fraction (PDFF)
• Change in visceral adipose tissue (VAT) volume by Magnetic Resonance Imaging (MRI)
• Change in NASH histology as assessed by the continuous NAFLD activity score (NAS), which measures different components of NASH on liver biopsy.
• Biochemical endpoints: serum lipids & HOMA-IR
• Feasibility outcomes including Rates (and reasons) for the following: a) % women that decline/women contacted for study inclusion (i.e. concern regarding randomization to placebo) b) % women enrolled/women screened (i.e. exclusion criteria too narrow), c) study dropout (i.e. medication side effects, too frequent study visits, and/or phlebotomy)

Inclusion criteria

• Women aged 18-42 years with hyperandrogenic PCOS
• NASH identified on liver biopsy or probable NASH on transient elastography- controlled attenuation parameter (TE-CAP) with cutoffs defined as CAP score ≥270 decibel/m and TE score > 7.0 kPA or alanine aminotransferase ≥40 U/L).

Exclusion criteria

• Uncontrolled diabetes
• Alcohol consumption >2 drinks per day for at least 3 consecutive months over the previous 5 years
• Other chronic liver disease (i.e. hepatitis B virus, hepatitis C virus, autoimmune hepatitis) or cirrhosis from any cause
• Recent or planned upcoming weight reduction surgery within five years of diagnosis of biopsy-confirmed NASH
• HIV infection
• Drugs associated with fatty liver (i.e. amiodarone, methotrexate, systemic glucocorticoids, tamoxifen, anabolic steroids, valproic acid) for more than 4 weeks prior to baseline or during study
• Recent, current, or planned upcoming pregnancy or current perimenopausal status
• Renal impairment (glomerular filtration rate <45 ml/min/1.73m or potassium levels > 5.0 mmol/L)
• Androgen receptor antagonist use (i.e. spironolactone or flutamide) for more than 3 months within one year prior to baseline