Pilot Randomized Controlled Trial of Spironolactone in Young Women With Nonalcoholic Steatohepatitis (NASH)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 20
- 试验地点
- 1
- 主要终点
- Change in Liver Stiffness on Magnetic Resonance Elastography (MRE)
研究概览
简要总结
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.
详细描述
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)
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Other
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
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.
入排标准
- 年龄范围
- 18 Years 至 45 Years（Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Women 18-45 years of age at Baseline Visit.
- •Documentation of NASH diagnosis confirmed on baseline liver biopsy (performed as clinical care) prior to study enrollment.
- •Written informed consent (and assent when applicable) obtained from subject and ability for subject to comply with the requirements of the study.
排除标准
- •Pregnant, breastfeeding, or unwilling to practice birth control during participation in the study
- •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
- •Uncontrolled diabetes (HbA1c 9.5% or higher within 60 days prior to enrollment)
- •Routine alcohol consumption >7 drinks per week during the preceding 3 months prior to baseline liver biopsy.
- •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
- •Any prior or upcoming weight reduction surgery (e.g., Roux-en-Y or gastric bypass)
- •HIV infection
- •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
- •Perimenopausal status (defined as within 3 years of self-reported menopause) due to unstable hormonal levels during that time
- •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
- •Participation in another clinical trial of an investigational drug or device
- •History of medication non adherence as noted upon chart review or patient report of difficulty with medication adherence
- •Androgen receptor antagonist use (i.e. flutamine, spironolactone or flutamide) for more than 3 months within one year prior to baseline biopsy
- •Eplerenone use as this is a diuretic that also blocks the aldosterone receptor and could compound side effects
- •Cirrhosis on baseline biopsy as this condition leads to altered sex hormone metabolism
- •Unstable dosing (i.e. dose increase, intermittent use, or initiation) of Vitamin E anytime during the 3 months prior to baseline biopsy
- •Significant weight loss (at least 10% decrease in body weight) over preceding 3 months prior to baseline biopsy
- •Contraindication to MRI scanning (e.g. presence of permanent pacemakers, implanted cardiac devices, etc.)
研究组 & 干预措施
spironolactone
spironolactone, 100 mg capsule administered orally once daily for 6 or 12 months
干预措施: Spironolactone 100mg (Drug)
placebo
matching placebo capsule administered orally once daily for 6 or 12 months
干预措施: Placebo oral capsule (Drug)
结局指标
主要结局
Change in Liver Stiffness on Magnetic Resonance Elastography (MRE)
时间窗: 6 or 12 Months
The investigators will assess for change in the MRE quantified liver stiffness in kilopascals (kPA)
次要结局
- Change in Hepatic Steatosis by Magnetic Resonance Proton Density Fat Fraction (PDFF)(6 or 12 months)
- Change in Visceral Adipose Tissue (VAT) Volume by Magnetic Resonance Imaging (MRI)(6 or 12 months)
- Change HOMA-IR (Homeostatic Model Assessment (HOMA) for Insulin Resistance (IR)).(6 or 12 Months)
- Change in the Non-Alcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS 0-8).(6 or 12 Months)