NASH - Nonalcoholic Steatohepatitis
Conditions
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)
Interventions
Spironolactone capsules will be prepared from USP grade powder at a dose of 100 mg.
DRUGPlacebo oral capsule
Matching placebo capsules of the same color, mass, and appearance to the spironolactone capsules will be filled using microcrystalline cellulose powder.
Sponsors
University of California, San Francisco
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
QUADRUPLE (Subject, Caregiver, 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.
Intervention model description
The following treatment regimens will be used: * Experimental treatment - spironolactone, 100 mg once daily * Placebo or Comparator - one capsule, once daily
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 45 Years
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.)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| Change in Visceral Adipose Tissue (VAT) Volume by Magnetic Resonance Imaging (MRI) | 6 or 12 months | The investigators will assess for change in the MRI quantified VAT volume cm\^2 |
| 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. HOMA-IR was calculated as: Fasting serum insulin (mU/L) x Fasting plasma glucose (mmol/L) / 22.5. Higher scores indicate greater insulin resistance and a worse outcome. There is no theoretical minimum and/or maximum value for HOMA-IR. |
| Change in the Non-Alcoholic Fatty Liver Disease (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). The NAS scoring is used to assess the severity and activity of NAFLD taking into account three components: steatosis (fat accumulation) scored from 0 to 3, Lobular inflammation scored from 0 to 3, and hepatocyte ballooning scored from 0 to 2. The total NAS score ranges from 0 to 8. Higher scores indicate greater disease activity. Interpretation of NAS scores: 0-2 no significant NAFLD, 3-4, borderline NASH, and 5-8, definite NASH. As this was an optional component of the study, none of the participants who completed 6 months chose to undergo the biopsy which is why we only have 12 month measurements. |
Countries
United States
Participant flow
Pre-assignment details
Three patients withdrew consent prior to randomization. All other participants were immediately randomized once baseline was completed.
Participants by arm
| Arm | Count |
|---|---|
| Spironolactone spironolactone, 100 mg capsule administered orally once daily for 6 or 12 months
Spironolactone 100mg: Spironolactone capsules will be prepared from USP grade powder at a dose of 100 mg. | 11 |
| Placebo matching placebo capsule administered orally once daily for 6 or 12 months
Placebo oral capsule: Matching placebo capsules of the same color, mass, and appearance to the spironolactone capsules will be filled using microcrystalline cellulose powder. | 6 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Spironolactone | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants | 6 Participants | 17 Participants |
| Age, Continuous | 33 Years | 30 Years | 32 Years |
| Diagnosed with PCOS | 6 Participants | 2 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 4 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants | 2 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 5 Participants | 14 Participants |
| Region of Enrollment United States | 11 Participants | 6 Participants | 17 Participants |
| Sex: Female, Male Female | 11 Participants | 6 Participants | 17 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 0 / 6 |
| other Total, other adverse events | 6 / 11 | 4 / 6 |
| serious Total, serious adverse events | 0 / 11 | 0 / 6 |
Outcome results
Primary
Change in Liver Stiffness on Magnetic Resonance Elastography (MRE)
The investigators will assess for change in the MRE quantified liver stiffness in kilopascals (kPA)
Time frame: 6 or 12 Months
Population: Median (IQR) change in kPA will be reported from baseline to 6 months and separately baseline to 12 months by treatment group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Spironolactone 6 | Change in Liver Stiffness on Magnetic Resonance Elastography (MRE) | 0.025 Change in kPA |
| Placebo 6 | Change in Liver Stiffness on Magnetic Resonance Elastography (MRE) | -0.265 Change in kPA |
| Sprionolactone 12 | Change in Liver Stiffness on Magnetic Resonance Elastography (MRE) | 0.105 Change in kPA |
| Placebo 12 | Change in Liver Stiffness on Magnetic Resonance Elastography (MRE) | 0.135 Change in kPA |
Secondary
Change HOMA-IR (Homeostatic Model Assessment (HOMA) for Insulin Resistance (IR)).
The investigators will assess change in continuous measures of HOMA-IR as insulin resistance is known to contribute to NASH progression. HOMA-IR was calculated as: Fasting serum insulin (mU/L) x Fasting plasma glucose (mmol/L) / 22.5. Higher scores indicate greater insulin resistance and a worse outcome. There is no theoretical minimum and/or maximum value for HOMA-IR.
Time frame: 6 or 12 Months
Population: Median (IQR) change will be reported (mU/L\*mmol/L) from baseline to 6 months and separately from baseline to 12 months by treatment group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Spironolactone 6 | Change HOMA-IR (Homeostatic Model Assessment (HOMA) for Insulin Resistance (IR)). | 5.29 mU/L*mmol/L |
| Placebo 6 | Change HOMA-IR (Homeostatic Model Assessment (HOMA) for Insulin Resistance (IR)). | 4.49 mU/L*mmol/L |
| Sprionolactone 12 | Change HOMA-IR (Homeostatic Model Assessment (HOMA) for Insulin Resistance (IR)). | 5.99 mU/L*mmol/L |
| Placebo 12 | Change HOMA-IR (Homeostatic Model Assessment (HOMA) for Insulin Resistance (IR)). | 11.90 mU/L*mmol/L |
Secondary
Change in Hepatic Steatosis by Magnetic Resonance Proton Density Fat Fraction (PDFF)
The investigators will assess for % change in fat fraction by MRI-PDFF
Time frame: 6 or 12 months
Population: Standard error change in % will be reported from baseline to 6 months and separately baseline to 12 months by treatment group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Spironolactone 6 | Change in Hepatic Steatosis by Magnetic Resonance Proton Density Fat Fraction (PDFF) | -4.95 % change |
| Placebo 6 | Change in Hepatic Steatosis by Magnetic Resonance Proton Density Fat Fraction (PDFF) | -3.05 % change |
| Sprionolactone 12 | Change in Hepatic Steatosis by Magnetic Resonance Proton Density Fat Fraction (PDFF) | -5.20 % change |
| Placebo 12 | Change in Hepatic Steatosis by Magnetic Resonance Proton Density Fat Fraction (PDFF) | -3.20 % change |
Secondary
Change in the Non-Alcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS 0-8).
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). The NAS scoring is used to assess the severity and activity of NAFLD taking into account three components: steatosis (fat accumulation) scored from 0 to 3, Lobular inflammation scored from 0 to 3, and hepatocyte ballooning scored from 0 to 2. The total NAS score ranges from 0 to 8. Higher scores indicate greater disease activity. Interpretation of NAS scores: 0-2 no significant NAFLD, 3-4, borderline NASH, and 5-8, definite NASH. As this was an optional component of the study, none of the participants who completed 6 months chose to undergo the biopsy which is why we only have 12 month measurements.
Time frame: 6 or 12 Months
Population: Median (IQR) change will be reported from baseline to 12 months by treatment group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Spironolactone 6 | Change in the Non-Alcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS 0-8). | 2 scores on a scale |
| Placebo 6 | Change in the Non-Alcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS 0-8). | 2.5 scores on a scale |
Secondary
Change in Visceral Adipose Tissue (VAT) Volume by Magnetic Resonance Imaging (MRI)
The investigators will assess for change in the MRI quantified VAT volume cm\^2
Time frame: 6 or 12 months
Population: Median (IQR) change in cm\^2 will be reported from baseline to 6 months and separately baseline to 12 months by treatment group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Spironolactone 6 | Change in Visceral Adipose Tissue (VAT) Volume by Magnetic Resonance Imaging (MRI) | 3.3 cm^2 |
| Placebo 6 | Change in Visceral Adipose Tissue (VAT) Volume by Magnetic Resonance Imaging (MRI) | 11.9 cm^2 |
| Sprionolactone 12 | Change in Visceral Adipose Tissue (VAT) Volume by Magnetic Resonance Imaging (MRI) | 6.8 cm^2 |
| Placebo 12 | Change in Visceral Adipose Tissue (VAT) Volume by Magnetic Resonance Imaging (MRI) | 18.3 cm^2 |