Spironolactone Therapy In Young Women With NASH
| Status: | Recruiting |
|---|---|
| Conditions: | Gastrointestinal |
| Therapuetic Areas: | Gastroenterology |
| Healthy: | No |
| Age Range: | 18 - 45 |
| Updated: | 1/17/2019 |
| Start Date: | January 9, 2019 |
| End Date: | September 2023 |
| Contact: | Monika A Sarkar, MD, MAS |
| Email: | monika.sarkar@ucsf.edu |
| Phone: | (415) 502-2656 |
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.
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.
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 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 12 months.
In person evaluations will take place at Month 1, 3, 6, 9, 12, and at the follow up visit
within 3 months of end of treatment (up to Month 15).
This is a pilot clinical trial that is largely feasibility focused. Study outcomes will
include
- 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)
pilot clinical trial of spironolactone in women with biopsy-proven NASH receiving 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 12 months.
In person evaluations will take place at Month 1, 3, 6, 9, 12, and at the follow up visit
within 3 months of end of treatment (up to Month 15).
This is a pilot clinical trial that is largely feasibility focused. Study outcomes will
include
- 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)
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) within one year of 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-antitryspin 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. Epleronone 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 6 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.)
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