Clinical trial NCT03576755: Spironolactone Therapy In Young Women With NASH
Official title: Pilot Randomized Controlled Trial of Spironolactone in Young Women With Nonalcoholic Steatohepatitis (NASH)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: NASH - Nonalcoholic Steatohepatitis
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
First posted: 2018-07-03
Enrollment: 20
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The following treatment regimens will be used:

* Experimental treatment - spironolactone, 100 mg once daily
* Placebo or Comparator - one capsule, once daily
Primary purpose: OTHER

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)

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.)

Primary outcomes:
measure: Change in Liver Stiffness on Magnetic Resonance Elastography (MRE)
timeFrame: 6 or 12 Months
Secondary outcomes:
measure: Change in Hepatic Steatosis by Magnetic Resonance Proton Density Fat Fraction (PDFF)
timeFrame: 6 or 12 months
measure: Change in Visceral Adipose Tissue (VAT) Volume by Magnetic Resonance Imaging (MRI)
timeFrame: 6 or 12 months
measure: Change HOMA-IR (Homeostatic Model Assessment (HOMA) for Insulin Resistance (IR)).
timeFrame: 6 or 12 Months
measure: Change in the Non-Alcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS 0-8).
timeFrame: 6 or 12 Months
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
Study officials:
affiliation: University of California, San Francisco
name: Monika A Sarkar
role: PRINCIPAL_INVESTIGATOR
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