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Spironolactone Therapy In Young Women With NASH

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ClinicalTrials.gov Identifier: NCT03576755
Recruitment Status : Recruiting
First Posted : July 3, 2018
Last Update Posted : January 15, 2019
Sponsor:
Information provided by (Responsible Party):
Monika Sarkar, MD, University of California, San Francisco

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
NASH - Nonalcoholic Steatohepatitis 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 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)

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Study Type : Interventional  (Clinical Trial)
Estimated 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 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 : January 9, 2019
Estimated Primary Completion Date : July 2023
Estimated Study Completion Date : September 2023


Arm Intervention/treatment
Experimental: spironolactone
spironolactone, 100 mg capsule administered orally once daily for 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 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.




Primary Outcome Measures :
  1. Change in the NAFLD activity score (NAS 0-8) [ Time Frame: 12 Months ]
    The investigators will assess for change in this histologic scoring system of NASH as a continuous measure


Secondary Outcome Measures :
  1. Change HOMA-IR (Homeostatic model assessment (HOMA) for insulin resistance (IR)) [ Time Frame: 12 Months ]
    The investigators will assess change in continuous measures of HOMA-IR as insulin resistance is known to contribute to NASH progression.



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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03576755


Contacts
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Contact: Monika A Sarkar, MD, MAS (415) 502-2656 monika.sarkar@ucsf.edu
Contact: Norah Terrault, MD, MPH (415) 353-2318 Norah.terrault@ucsf.edu

Locations
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United States, California
University of California San Francisco Recruiting
San Francisco, California, United States, 94143
Contact: Monika A Sarkar, MD    415-502-2656    monika.sarkar@ucsf.edu   
Sponsors and Collaborators
Monika Sarkar, MD

Publications:

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Responsible Party: Monika Sarkar, MD, Assistant Clinical Professor of Medicine, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT03576755     History of Changes
Other Study ID Numbers: 18-24453
First Posted: July 3, 2018    Key Record Dates
Last Update Posted: January 15, 2019
Last Verified: January 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Fatty Liver
Non-alcoholic Fatty Liver Disease
Liver Diseases
Digestive System Diseases
Spironolactone
Mineralocorticoid Receptor Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Diuretics, Potassium Sparing
Diuretics
Natriuretic Agents