Bicalutamide Therapy in Young Women With NAFLD and PCOS

Официальное название

Pilot Trial of Bicalutamide Versus Placebo in Reproductive-Aged Women With Nonalcoholic Fatty Liver Disease (NAFLD) and Polycystic Ovary Syndrome (PCOS)

Обзор

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. This study will study the contribution of androgens to liver injury and progression in PCOS and mechanistic role of dysregulated lipid metabolism and visceral adiposity in this process. Such findings will provide the rationale for future efficacy studies evaluating selective androgen receptor (AR) antagonism for NASH in PCOS, or alternatively, the need to directly target visceral adiposity or lipid-specific pathways as part of a precision medicine approach to halt fibrosis progression in the nearly 5 million young women with PCOS and NAFLD in the U.S., who remain at increased risk for early onset and progressive liver disease.

Подробное описание

This is a single center, double-blind, placebo-controlled, randomized, (1:1) parallel group pilot clinical trial of bicalutamide in women with either biopsy-proven or believed NAFLD receiving 6 months of bicalutamide or placebo. 50 women are targeted for enrollment. Each participant will be administered a single dose of bicalutamide or placebo once daily for a total of 6 months. In person evaluations will take place at Month 1, 2, 3, 4, 5, and 6. There will be a telephone follow up visit within 1 month of end of treatment. 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. 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)

Вмешательства

• Препарат Bicalutamide 50 mg
  Bicalutamide capsules will be prepared from U.S. Pharmacopeia grade powder at a dose of 50 mg
• Препарат Placebo
  Matching placebo capsules of the same color, mass, and appearance to the bicalutamide capsules will be filled using microcrystalline cellulose powder.

Первичные конечные точки

• Change in liver stiffness on Magnetic Resonance Elastography (MRE) [Срок оценки: Baseline and 6 months]

Вторичные конечные точки (4)

• Change in hepatic steatosis by Magnetic Resonance Proton Density Fat Fraction (PDFF) [Срок оценки: Baseline and 6 months]
• Change in visceral adipose tissue (VAT) volume by Magnetic Resonance Imaging (MRI) [Срок оценки: Baseline and 6 months]
• Change HOMA-IR (Homeostatic model assessment (HOMA) for insulin resistance (IR)) [Срок оценки: Baseline and 6 months]
• Change in the NAFLD Activity Score (NAS) on a scale from 0 (low activity) to 8 (high activity) [Срок оценки: Baseline and 6 months]

Критерии участия

Критерии включения

• Women aged 18-42 years with hyperandrogenic PCOS
• NASH identified on liver biopsy or probable NASH on transient elastography- controlled attenuation parameter (TE-CAP) with cutoffs defined as CAP score ≥270 decibel/m and TE score > 7.0 kPA or alanine aminotransferase ≥40 U/L).

Критерии исключения

• Uncontrolled diabetes
• Alcohol consumption >2 drinks per day for at least 3 consecutive months over the previous 5 years
• Other chronic liver disease (i.e. hepatitis B virus, hepatitis C virus, autoimmune hepatitis) or cirrhosis from any cause
• Recent or planned upcoming weight reduction surgery within five years of diagnosis of biopsy-confirmed NASH
• HIV infection
• Drugs associated with fatty liver (i.e. amiodarone, methotrexate, systemic glucocorticoids, tamoxifen, anabolic steroids, valproic acid) for more than 4 weeks prior to baseline or during study
• Recent, current, or planned upcoming pregnancy or current perimenopausal status
• Renal impairment (glomerular filtration rate <45 ml/min/1.73m or potassium levels > 5.0 mmol/L)
• Androgen receptor antagonist use (i.e. spironolactone or flutamide) for more than 3 months within one year prior to baseline

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Четверное слепое

Основная цель

Другое

Центры проведения

США · 1 центр

• University of California San Francisco — San Francisco

Публикации

• Maldonado SS, Grab J, Wang CW, Huddleston H, Cedars M, Sarkar M. Polycystic ovary syndrome is associated with nonalcoholic steatohepatitis in women of reproductive age. Hepatol Commun. 2022 Oct;6(10):2634-2639. doi: 10.1002/hep4.2039. Epub 2022 Jul 21. PMID 35861548
• Sarkar MA, Suzuki A, Abdelmalek MF, Yates KP, Wilson LA, Bass NM, Gill R, Cedars M, Terrault N; NASH Clinical Research Network. Testosterone is Associated With Nonalcoholic Steatohepatitis and Fibrosis in Premenopausal Women With NAFLD. Clin Gastroenterol Hepatol. 2021 Jun;19(6):1267-1274.e1. doi: 10.1016/j.cgh.2020.09.045. Epub 2020 Oct 1. PMID 33010412
• Sanchez-Garrido MA, Tena-Sempere M. Metabolic dysfunction in polycystic ovary syndrome: Pathogenic role of androgen excess and potential therapeutic strategies. Mol Metab. 2020 May;35:100937. doi: 10.1016/j.molmet.2020.01.001. Epub 2020 Feb 5. PMID 32244180
• O'Reilly MW, Kempegowda P, Walsh M, Taylor AE, Manolopoulos KN, Allwood JW, Semple RK, Hebenstreit D, Dunn WB, Tomlinson JW, Arlt W. AKR1C3-Mediated Adipose Androgen Generation Drives Lipotoxicity in Women With Polycystic Ovary Syndrome. J Clin Endocrinol Metab. 2017 Sep 1;102(9):3327-3339. doi: 10.1210/jc.2017-00947. PMID 28645211
• Dieudonne MN, Pecquery R, Boumediene A, Leneveu MC, Giudicelli Y. Androgen receptors in human preadipocytes and adipocytes: regional specificities and regulation by sex steroids. Am J Physiol. 1998 Jun;274(6):C1645-52. doi: 10.1152/ajpcell.1998.274.6.C1645. PMID 9611130
• Gambineri A, Patton L, Vaccina A, Cacciari M, Morselli-Labate AM, Cavazza C, Pagotto U, Pasquali R. Treatment with flutamide, metformin, and their combination added to a hypocaloric diet in overweight-obese women with polycystic ovary syndrome: a randomized, 12-month, placebo-controlled study. J Clin Endocrinol Metab. 2006 Oct;91(10):3970-80. doi: 10.1210/jc.2005-2250. Epub 2006 Jul 25. PMID 16868063
• Cusi K. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. Gastroenterology. 2012 Apr;142(4):711-725.e6. doi: 10.1053/j.gastro.2012.02.003. Epub 2012 Feb 8. PMID 22326434
• Macut D, Tziomalos K, Bozic-Antic I, Bjekic-Macut J, Katsikis I, Papadakis E, Andric Z, Panidis D. Non-alcoholic fatty liver disease is associated with insulin resistance and lipid accumulation product in women with polycystic ovary syndrome. Hum Reprod. 2016 Jun;31(6):1347-53. doi: 10.1093/humrep/dew076. Epub 2016 Apr 12. PMID 27076501

Идентификаторы

NCT: NCT05979389 · 23-39274 · R01DK134633-01A1

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗