Spironolactone Therapy In Young Women With NASH

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. 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.

Detailed Description
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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)

Official Title
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Pilot Randomized Controlled Trial of Spironolactone in Young Women With Nonalcoholic Steatohepatitis (NASH)

Conditions
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NASH - Nonalcoholic Steatohepatitis

Intervention / Treatment
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* Drug: Spironolactone 100mg
* Drug: Placebo oral capsule


Participation Criteria
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Eligibility Criteria
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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.)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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 - spironolactone, 100 mg once daily Placebo or Comparator - one capsule, once daily
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: spironolactone<br>spironolactone, 100 mg capsule administered orally once daily for 6 or 12 months | Drug: Spironolactone 100mg<br>* Spironolactone capsules will be prepared from USP grade powder at a dose of 100 mg.<br>|
| Placebo Comparator: placebo<br>matching placebo capsule administered orally once daily for 6 or 12 months | Drug: Placebo oral capsule<br>* Matching placebo capsules of the same color, mass, and appearance to the spironolactone 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) | 6 or 12 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 % change in fat fraction by MRI-PDFF | 6 or 12 months | 
| Change in visceral adipose tissue (VAT) volume by Magnetic Resonance Imaging (MRI) | The investigators will assess for % change in VAT as quantified by MRI | 6 or 12 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. | 6 or 12 Months | 
| Change in the NAFLD activity score (NAS 0-8). | 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). | 6 or 12 Months |