Spironolactone Therapy In Young Women With NASH

NCT03576755 | Completed Phase 1 Results DMC FDA Drug

• 1 other identifier: 18-24453
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

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.

Conditions

NASH - Nonalcoholic Steatohepatitis

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (4)

• Change in Hepatic Steatosis by Magnetic Resonance Proton Density Fat Fraction (PDFF)

  6 or 12 months

• Change in Visceral Adipose Tissue (VAT) Volume by Magnetic Resonance Imaging (MRI)

  6 or 12 months

• Change HOMA-IR (Homeostatic Model Assessment (HOMA) for Insulin Resistance (IR)).

  6 or 12 Months

• Change in the Non-Alcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS 0-8).

  6 or 12 Months

Study Arms (2)

spironolactone

EXPERIMENTAL

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

Drug: Spironolactone 100mg

placebo

PLACEBO COMPARATOR

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

Drug: Placebo oral capsule

Interventions

Spironolactone 100mg DRUG

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

spironolactone

Placebo oral capsule DRUG

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

placebo

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• University of California, San Francisco: lead

Study Sites (1)

University of California San Francisco

San Francisco, California, 94143, United States

Location

Related Publications (13)

• 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.

  PMID: 21726509 BACKGROUND

• 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.

  PMID: 24375711 BACKGROUND

• 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.

  PMID: 28291240 BACKGROUND

• 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.

  PMID: 22488764 BACKGROUND

• 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.

  PMID: 21987488 BACKGROUND

• 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.

  PMID: 20648476 BACKGROUND

• 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.

  PMID: 25339805 BACKGROUND

• 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.

  PMID: 25024594 BACKGROUND

• 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.

  PMID: 27076501 BACKGROUND

• 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.

  PMID: 8964851 BACKGROUND

• 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.

  PMID: 18615851 BACKGROUND

• 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.

  PMID: 9275065 BACKGROUND

• 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.

  PMID: 20211973 BACKGROUND

MeSH Terms

Conditions

Non-alcoholic Fatty Liver Disease

Interventions

Canrenoic Acid

Condition Hierarchy (Ancestors)

Fatty Liver; Liver Diseases; Digestive System Diseases

Intervention Hierarchy (Ancestors)

Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Results Point of Contact

• Title: Principal Investigator: Dr. Monika Sarkar
• Organization: University of California San Francisco

monika.sarkar@ucsf.edu

415-502-2656

Study Officials

• Monika A Sarkar

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Due to the objectives of the study, the identity of test and control treatments will not be known to investigators, research staff, or patients. The following study procedures will be in place to ensure double-blind administration of study treatments Access to the randomization code will be strictly controlled. A color and size-matched placebo capsule that looks identical to the spironolactone capsule will be used. Packaging and labeling of test and control treatments will be identical to maintain the blind. The study blind will be broken on completion of the clinical study, after all study endpoints have been ascertained by blinded study coordinators and after the study database has been locked. During the study, the blind may be broken only in emergencies when knowledge of the patient's treatment group is necessary for further patient management. The UCSF investigational pharmacy would then be notified and responsible for unblinding.
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The following treatment regimens will be used: * Experimental treatment - spironolactone, 100 mg once daily * Placebo or Comparator - one capsule, once daily

Study Record Dates

• First Submitted: April 18, 2018
• First Posted: July 3, 2018
• Study Start: January 9, 2019
• Primary Completion: July 5, 2023
• Study Completion: July 5, 2023
• Last Updated: March 26, 2025
• Results First Posted: March 26, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)