Spironolactone Therapy In Young Women With NASH

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

• Women 18-45 years of age at Baseline Visit.
• Documentation of NASH diagnosis confirmed on baseline liver biopsy (performed as clinical care) prior to study enrollment.
• Written informed consent (and assent when applicable) obtained from subject and ability for subject to comply with the requirements of the study.

Exclusion criteria

• Pregnant, breastfeeding, or unwilling to practice birth control during participation in the study
• 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
• Uncontrolled diabetes (HbA1c 9.5% or higher within 60 days prior to enrollment)
• Routine alcohol consumption >7 drinks per week during the preceding 3 months prior to baseline liver biopsy.
• 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
• Any prior or upcoming weight reduction surgery (e.g., Roux-en-Y or gastric bypass)
• HIV infection
• 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
• Perimenopausal status (defined as within 3 years of self-reported menopause) due to unstable hormonal levels during that time
• 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
• Participation in another clinical trial of an investigational drug or device
• History of medication non adherence as noted upon chart review or patient report of difficulty with medication adherence
• Androgen receptor antagonist use (i.e. flutamine, spironolactone or flutamide) for more than 3 months within one year prior to baseline biopsy
• Eplerenone use as this is a diuretic that also blocks the aldosterone receptor and could compound side effects
• Cirrhosis on baseline biopsy as this condition leads to altered sex hormone metabolism
• Unstable dosing (i.e. dose increase, intermittent use, or initiation) of Vitamin E anytime during the 3 months prior to baseline biopsy
• Significant weight loss (at least 10% decrease in body weight) over preceding 3 months prior to baseline biopsy
• Contraindication to MRI scanning (e.g. presence of permanent pacemakers, implanted cardiac devices, etc.)