Spironolactone Therapy In Young Women With NASH

NCT ID: NCT03576755

Last Updated: 2025-03-26

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 20 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-01-09
• Study Completion Date: 2023-07-05

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.

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

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)

Conditions

NASH - Nonalcoholic Steatohepatitis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: OTHER
• Blinding Strategy: QUADRUPLE

Study Groups

spironolactone

spironolactone, 100 mg capsule administered orally once daily for 6 or 12 months

Group Type: EXPERIMENTAL

Spironolactone 100mg

Intervention Type: DRUG

Spironolactone capsules will be prepared from USP grade powder at a dose of 100 mg.

placebo

matching placebo capsule administered orally once daily for 6 or 12 months

Group Type: PLACEBO_COMPARATOR

Placebo oral capsule

Intervention Type: DRUG

Matching placebo capsules of the same color, mass, and appearance to the spironolactone capsules will be filled using microcrystalline cellulose powder.

Interventions

Spironolactone 100mg

Spironolactone capsules will be prepared from USP grade powder at a dose of 100 mg.

Intervention Type: 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.

Intervention Type: DRUG

Eligibility Criteria

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.)

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 45 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

University of California, San Francisco

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Monika A Sarkar

Role: PRINCIPAL_INVESTIGATOR

University of California, San Francisco

Locations

University of California San Francisco

San Francisco, California, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 21726509 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 24375711 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 28291240 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 22488764 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 21987488 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 20648476 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 25339805 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 25024594 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 27076501 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 8964851 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 18615851 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 9275065 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 20211973 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

18-24453

Identifier Type: -

Identifier Source: org_study_id