Spironolactone Therapy In Young Women With NASH

Pilot Randomized Controlled Trial of Spironolactone in Young Women With Nonalcoholic Steatohepatitis (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.

Study Overview

• Status: Completed
• Conditions: NASH - Nonalcoholic Steatohepatitis
• Intervention / Treatment: Drug: Spironolactone 100mg; Drug: Placebo oral capsule

Detailed Description

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)

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Monika A Sarkar, MD, MAS; Phone Number: (415) 502-2656; Email: monika.sarkar@ucsf.edu
• Study Contact Backup: Name: Marcelle Cedars, MD; Phone Number: (415)-353-3032; Email: marcelle.cedars@ucsf.edu

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94143
      • University of California San Francisco

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No

Description

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.)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: spironolactone; spironolactone, 100 mg capsule administered orally once daily for 6 or 12 months	Drug: Spironolactone 100mg; Spironolactone capsules will be prepared from USP grade powder at a dose of 100 mg.
Placebo Comparator: placebo; matching placebo capsule administered orally once daily for 6 or 12 months	Drug: Placebo oral capsule; Matching placebo capsules of the same color, mass, and appearance to the spironolactone capsules will be filled using microcrystalline cellulose powder.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Investigators: Principal Investigator: Monika A Sarkar, University of California, San Francisco

Publications and helpful links

General Publications

• Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, Charlton M, Sanyal AJ. The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology. 2012 Jun;55(6):2005-23. doi: 10.1002/hep.25762. No abstract available.
• Wong RJ, Cheung R, Ahmed A. Nonalcoholic steatohepatitis is the most rapidly growing indication for liver transplantation in patients with hepatocellular carcinoma in the U.S. Hepatology. 2014 Jun;59(6):2188-95. doi: 10.1002/hep.26986. Epub 2014 Apr 25.
• Kelley CE, Brown AJ, Diehl AM, Setji TL. Review of nonalcoholic fatty liver disease in women with polycystic ovary syndrome. World J Gastroenterol. 2014 Oct 21;20(39):14172-84. doi: 10.3748/wjg.v20.i39.14172.
• Charlton MR, Burns JM, Pedersen RA, Watt KD, Heimbach JK, Dierkhising RA. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology. 2011 Oct;141(4):1249-53. doi: 10.1053/j.gastro.2011.06.061. Epub 2011 Jul 2.
• Sarkar M, Wellons M, Cedars MI, VanWagner L, Gunderson EP, Ajmera V, Torchen L, Siscovick D, Carr JJ, Terry JG, Rinella M, Lewis CE, Terrault N. Testosterone Levels in Pre-Menopausal Women are Associated With Nonalcoholic Fatty Liver Disease in Midlife. Am J Gastroenterol. 2017 May;112(5):755-762. doi: 10.1038/ajg.2017.44. Epub 2017 Mar 14.
• Bambha K, Belt P, Abraham M, Wilson LA, Pabst M, Ferrell L, Unalp-Arida A, Bass N; Nonalcoholic Steatohepatitis Clinical Research Network Research Group. Ethnicity and nonalcoholic fatty liver disease. Hepatology. 2012 Mar;55(3):769-80. doi: 10.1002/hep.24726.
• Neuschwander-Tetri BA, Clark JM, Bass NM, Van Natta ML, Unalp-Arida A, Tonascia J, Zein CO, Brunt EM, Kleiner DE, McCullough AJ, Sanyal AJ, Diehl AM, Lavine JE, Chalasani N, Kowdley KV; NASH Clinical Research Network. Clinical, laboratory and histological associations in adults with nonalcoholic fatty liver disease. Hepatology. 2010 Sep;52(3):913-24. doi: 10.1002/hep.23784.
• Vassilatou E. Nonalcoholic fatty liver disease and polycystic ovary syndrome. World J Gastroenterol. 2014 Jul 14;20(26):8351-63. doi: 10.3748/wjg.v20.i26.8351.
• Macut D, Tziomalos K, Bozic-Antic I, Bjekic-Macut J, Katsikis I, Papadakis E, Andric Z, Panidis D. Non-alcoholic fatty liver disease is associated with insulin resistance and lipid accumulation product in women with polycystic ovary syndrome. Hum Reprod. 2016 Jun;31(6):1347-53. doi: 10.1093/humrep/dew076. Epub 2016 Apr 12.
• Lovejoy JC, Bray GA, Bourgeois MO, Macchiavelli R, Rood JC, Greeson C, Partington C. Exogenous androgens influence body composition and regional body fat distribution in obese postmenopausal women--a clinical research center study. J Clin Endocrinol Metab. 1996 Jun;81(6):2198-203. doi: 10.1210/jcem.81.6.8964851.
• Corbould A. Effects of androgens on insulin action in women: is androgen excess a component of female metabolic syndrome? Diabetes Metab Res Rev. 2008 Oct;24(7):520-32. doi: 10.1002/dmrr.872.
• Croston GE, Milan LB, Marschke KB, Reichman M, Briggs MR. Androgen receptor-mediated antagonism of estrogen-dependent low density lipoprotein receptor transcription in cultured hepatocytes. Endocrinology. 1997 Sep;138(9):3779-86. doi: 10.1210/endo.138.9.5404.
• Wada T, Kenmochi H, Miyashita Y, Sasaki M, Ojima M, Sasahara M, Koya D, Tsuneki H, Sasaoka T. Spironolactone improves glucose and lipid metabolism by ameliorating hepatic steatosis and inflammation and suppressing enhanced gluconeogenesis induced by high-fat and high-fructose diet. Endocrinology. 2010 May;151(5):2040-9. doi: 10.1210/en.2009-0869. Epub 2010 Mar 8.

Study record dates

Study Major Dates

• Study Start (Actual): January 9, 2019
• Primary Completion (Actual): July 5, 2023
• Study Completion (Actual): July 5, 2023

Study Registration Dates

• First Submitted: April 18, 2018
• First Submitted That Met QC Criteria: June 22, 2018
• First Posted (Actual): July 3, 2018

Study Record Updates

• Last Update Posted (Actual): July 7, 2023
• Last Update Submitted That Met QC Criteria: July 5, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Agents; Diuretics; Hormone Antagonists; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Spironolactone
• Other Study ID Numbers: 18-24453

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No