NAFLD, PCOS
Conditions
Brief summary
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
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)
Interventions
Bicalutamide capsules will be prepared from U.S. Pharmacopeia grade powder at a dose of 50 mg
DRUGPlacebo
Matching placebo capsules of the same color, mass, and appearance to the bicalutamide capsules will be filled using microcrystalline cellulose powder.
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
University of California, San Francisco
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Due to the objectives of the study, the identity of test and control treatments will not be known to investigators, research staff, or patients. The following study procedures will be in place to ensure double-blind administration of study treatments Access to the randomization code will be strictly controlled. A color and size-matched placebo capsule that looks identical to the bicalutamide capsule will be used. Packaging and labeling of test and control treatments will be identical to maintain the blind. The study blind will be broken on completion of the clinical study, after all study endpoints have been ascertained by blinded study coordinators and after the study database has been locked. During the study, the blind may be broken only in emergencies when knowledge of the patient's treatment group is necessary for further patient management. The University of California San Francisco investigational pharmacy would then be notified and responsible for unblinding.
Intervention model description
The following treatment regimens will be used: * Experimental treatment - bicalutamide, 50 mg once daily * Placebo or Comparator - one capsule, once daily
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 42 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in liver stiffness on Magnetic Resonance Elastography (MRE) | Baseline and 6 months | The investigators will assess for change in the MRE quantified liver stiffness in kilopascals (kPA) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in hepatic steatosis by Magnetic Resonance Proton Density Fat Fraction (PDFF) | Baseline and 6 months | The investigators will assess for percent change in fat fraction by MRI-PDFF |
| Change in visceral adipose tissue (VAT) volume by Magnetic Resonance Imaging (MRI) | Baseline and 6 months | The investigators will assess for percent change in VAT as quantified by MRI |
| Change HOMA-IR (Homeostatic model assessment (HOMA) for insulin resistance (IR)) | Baseline and 6 months | The investigators will assess change in continuous measures of HOMA-IR as insulin resistance is known to contribute to NASH progression |
| Change in the NAFLD Activity Score (NAS) on a scale from 0 (low activity) to 8 (high activity) | Baseline and 6 months | 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). |
Countries
United States
Contacts
Primary ContactElle K Oberweis-Manion
Outcome results
None listed