Spironolactone Therapy In Young Women With NASH
Spironolactone Therapy In Young Women With NASH
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.

 The investigator's preliminary data support a detrimental role of androgens, or "male sex
 hormones" on fatty liver in women but no studies have evaluated whether androgens are
 associated with liver inflammation and/or scarring from fatty liver (aka NASH). To better
 understand the mechanism by which androgens might promote NASH and/or metabolic co-factors
 that contribute to NASH, the investigators are conducting a pilot clinical trial to primarily
 assess the feasibility of using an androgen blocking medication, spironolactone, in women
 with NASH. Spironolactone was selected because it is has been commonly prescribed for decades
 with good safety profile and tolerability to treat symptoms of high androgens, like acne and
 hirsutism in young women. Though primarily a feasibility-focused study, the investigators
 also aim to explore the pathways by which blocking testosterone receptors might alter the
 biologic processes that promote NASH and its associated metabolic co-morbidities in women.
This is a single center, double-blind, placebo-controlled, randomized, (2:1) parallel group
 pilot clinical trial of spironolactone in women with biopsy-proven NASH receiving 6 or 12
 months of spironolactone or placebo. 30 women are targeted for enrollment. Each participant
 will be administered a single dose of spironolactone or placebo once daily for a total of 6
 or 12 months. In person evaluations will take place at Month 1, 3, 6, 9, and 12. There will
 be a telephone follow up visit within 3 months of end of treatment (up to Month 9 or 15).

 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. need for a second liver biopsy,
 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:

 1. Women 18-45 years of age at Baseline Visit.

 2. Documentation of NASH diagnosis confirmed on baseline liver biopsy (performed as
 clinical care) prior to study enrollment.

 3. Written informed consent (and assent when applicable) obtained from subject and
 ability for subject to comply with the requirements of the study.

 Exclusion Criteria:

 1. Pregnant, breastfeeding, or unwilling to practice birth control during participation
 in the study

 2. Presence of a condition or abnormality that in the opinion of the Investigator would
 compromise the safety of the patient or the quality of the data

 3. Uncontrolled diabetes (HbA1c 9.5% or higher within 60 days prior to enrollment)

 4. Routine alcohol consumption >7 drinks per week during the preceding 3 months prior to
 baseline liver biopsy.

 5. Other forms of chronic liver disease including hepatitis B virus infection (hepatitis
 B surface antigen positive), chronic hepatitis C virus (HCV) infection (HCV Ab and HCV
 ribonucleic acid positive), autoimmune disorders (e.g., primary biliary cholangitis,
 primary sclerosing cholangitis, and autoimmune hepatitis), drug-induced
 hepatotoxicity, Wilson disease, iron overload, and alpha-1-antitrypsin deficiency,
 based on medical history and/or centralized review of liver histology

 6. Any prior or upcoming weight reduction surgery (e.g., Roux-en-Y or gastric bypass)

 7. HIV infection

 8. Receipt of drugs associated with NAFLD (i.e. amiodarone, methotrexate, systemic
 glucocorticoids, tamoxifen, anabolic steroids, valproic acid) for more than 4 weeks
 prior to baseline or between baseline and follow-up biopsies

 9. Perimenopausal status (defined as within 3 years of self-reported menopause) due to
 unstable hormonal levels during that time

 10. Renal impairment defined as glomerular filtration rate <45 ml/min/1.73m or potassium
 levels > 5.0 mmol/L due to the diuretic effect of spironolactone

 11. Participation in another clinical trial of an investigational drug or device

 12. History of medication non adherence as noted upon chart review or patient report of
 difficulty with medication adherence

 13. Androgen receptor antagonist use (i.e. flutamine, spironolactone or flutamide) for
 more than 3 months within one year prior to baseline biopsy

 14. Eplerenone use as this is a diuretic that also blocks the aldosterone receptor and
 could compound side effects

 15. Cirrhosis on baseline biopsy as this condition leads to altered sex hormone metabolism

 16. Unstable dosing (i.e. dose increase, intermittent use, or initiation) of Vitamin E
 anytime during the 3 months prior to baseline biopsy

 17. Significant weight loss (at least 10% decrease in body weight) over preceding 3 months
 prior to baseline biopsy

 18. Contraindication to MRI scanning (e.g. presence of permanent pacemakers, implanted
 cardiac devices, etc.)