Bicalutamide Therapy in Young Women With NAFLD and PCOS

Study Overview
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Brief Summary
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Nonalcoholic steatohepatitis (NASH), or fat-related liver inflammation and scarring is projected to be the leading cause of cirrhosis in the United States (U.S.) within the next few years. Women are at disproportionate risk for NASH, with approximately 15 million U.S. women affected. There is an urgent need to understand risk factors for NASH and its progression in women, and sex hormones may provide a missing link. This study will study the contribution of androgens to liver injury and progression in PCOS and mechanistic role of dysregulated lipid metabolism and visceral adiposity in this process. Such findings will provide the rationale for future efficacy studies evaluating selective androgen receptor (AR) antagonism for NASH in PCOS, or alternatively, the need to directly target visceral adiposity or lipid-specific pathways as part of a precision medicine approach to halt fibrosis progression in the nearly 5 million young women with PCOS and NAFLD in the U.S., who remain at increased risk for early onset and progressive liver disease.

Detailed Description
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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)

Official Title
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Pilot Trial of Bicalutamide Versus Placebo in Reproductive-Aged Women With Nonalcoholic Fatty Liver Disease (NAFLD) and Polycystic Ovary Syndrome (PCOS)

Conditions
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NAFLD, PCOS

Intervention / Treatment
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* Drug: Bicalutamide 50 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women aged 18-40 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The following treatment regimens will be used: Experimental treatment - bicalutamide, 50 mg once daily Placebo or Comparator - one capsule, once daily
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bicalutamide<br>50 mg capsule administered orally once daily for 6 months | Drug: Bicalutamide 50 mg<br>* Bicalutamide capsules will be prepared from U.S. Pharmacopeia grade powder at a dose of 50 mg<br>* Other names: Casodex;|
| Placebo Comparator: Placebo<br>Matching placebo capsule administered orally once daily for 6 months | Drug: Placebo<br>* Matching placebo capsules of the same color, mass, and appearance to the bicalutamide capsules will be filled using microcrystalline cellulose powder.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in liver stiffness on Magnetic Resonance Elastography (MRE) | The investigators will assess for change in the MRE quantified liver stiffness in kilopascals (kPA) | Baseline and 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in hepatic steatosis by Magnetic Resonance Proton Density Fat Fraction (PDFF) | The investigators will assess for percent change in fat fraction by MRI-PDFF | Baseline and 6 months | 
| Change in visceral adipose tissue (VAT) volume by Magnetic Resonance Imaging (MRI) | The investigators will assess for percent change in VAT as quantified by MRI | Baseline and 6 months | 
| Change HOMA-IR (Homeostatic model assessment (HOMA) for insulin resistance (IR)) | The investigators will assess change in continuous measures of HOMA-IR as insulin resistance is known to contribute to NASH progression | Baseline and 6 months | 
| Change in the NAFLD Activity Score (NAS) on a scale from 0 (low activity) to 8 (high activity) | The investigators will assess for change in this histologic scoring system of NASH as a continuous measure among women willing to undergo end of treatment biopsy (not required). | Baseline and 6 months |