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Spironolactone Therapy In Young Women With NASH

Sponsor
University of California, San Francisco (Other)
Overall Status
Recruiting
CT.gov ID
NCT03576755
Collaborator
(none)
30
Enrollment
1
Location
2
Arms
41.7
Anticipated Duration (Months)
0.7
Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
  • Drug: Spironolactone 100mg
  • Drug: Placebo oral capsule
 Phase 1/Phase 2

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 Design

Study Type:
Interventional
Anticipated Enrollment :
30 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Intervention Model Description:
The following treatment regimens will be used: Experimental treatment - spironolactone, 100 mg once daily Placebo or Comparator - one capsule, once dailyThe following treatment regimens will be used:Experimental treatment - spironolactone, 100 mg once daily Placebo or Comparator - one capsule, once daily
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:
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.
Primary Purpose:
Other
Official Title:
Pilot Randomized Controlled Trial of Spironolactone in Young Women With Nonalcoholic Steatohepatitis (NASH)
Actual Study Start Date :
Jan 9, 2019
Anticipated Primary Completion Date :
Jul 1, 2022
Anticipated Study Completion Date :
Jul 1, 2022

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures

  1. Change in liver stiffness on Magnetic Resonance Elastography (MRE) [6 or 12 Months]

    The investigators will assess for change in the MRE quantified liver stiffness in kilopascals (kPA)

Secondary Outcome Measures

  1. Change in hepatic steatosis by Magnetic Resonance Proton Density Fat Fraction (PDFF) [6 or 12 months]

    The investigators will assess for % change in fat fraction by MRI-PDFF

  2. Change in visceral adipose tissue (VAT) volume by Magnetic Resonance Imaging (MRI) [6 or 12 months]

    The investigators will assess for % change in VAT as quantified by MRI

  3. Change HOMA-IR (Homeostatic model assessment (HOMA) for insulin resistance (IR)). [6 or 12 Months]

    The investigators will assess change in continuous measures of HOMA-IR as insulin resistance is known to contribute to NASH progression.

  4. Change in the NAFLD activity score (NAS 0-8). [6 or 12 Months]

    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).

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years to 45 Years
Sexes Eligible for Study:
Female
Accepts Healthy Volunteers:
No
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.)

Contacts and Locations

Locations

Site City State Country Postal Code
1 University of California San Francisco San Francisco California United States 94143

Sponsors and Collaborators

  • University of California, San Francisco

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Publications

Responsible Party:
University of California, San Francisco
ClinicalTrials.gov Identifier:
NCT03576755
Other Study ID Numbers:
  • 18-24453
First Posted:
Jul 3, 2018
Last Update Posted:
Aug 25, 2021
Last Verified:
Aug 1, 2021
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Additional relevant MeSH terms:
Fatty Liver
Non-alcoholic Fatty Liver Disease
Spironolactone

Study Results

No Results Posted as of Aug 25, 2021