Bicalutamide Therapy in Young Women With NAFLD and PCOS

NAFLD Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05979389
• Other study ID #: 23-39274
• Secondary ID: R01DK134633-01A1
• Status: Recruiting
• Phase: Phase 1
• Start date: February 14, 2024
• Est. completion date: August 2028

Study information

• Verified date: May 2024
• Source: University of California, San Francisco
• Contact: Elle K Oberweis-Manion
• Phone: (415)-502-3725
• Email: elle.oberweismanion[@]ucsf.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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. 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.

Description:

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)

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 50
• Est. completion date: August 2028
• Est. primary completion date: August 2028
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 40 Years

Eligibility

Inclusion Criteria:

• Women aged 18-40 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).

Exclusion Criteria:

• 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

Related Conditions & MeSH terms

• NAFLD
• Non-alcoholic Fatty Liver Disease
• PCOS

Intervention

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

Locations

Country	Name	City	State
United States	University of California San Francisco	San Francisco	California

Sponsors (2)

Lead Sponsor	Collaborator
University of California, San Francisco	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Country where clinical trial is conducted

United States, 

References & Publications (11)

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. — View Citation

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. — View Citation

Fernandez-Nieto D, Saceda-Corralo D, Rodrigues-Barata R, Hermosa-Gelbard A, Moreno-Arrones O, Jimenez-Cauhe J, Ortega-Quijano D, Vano-Galvan S. Oral bicalutamide for female pattern hair loss: A pilot study. Dermatol Ther. 2019 Nov;32(6):e13096. doi: 10.1111/dth.13096. Epub 2019 Oct 10. No abstract available. — View Citation

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. — View Citation

Ismail FF, Meah N, Trindade de Carvalho L, Bhoyrul B, Wall D, Sinclair R. Safety of oral bicalutamide in female pattern hair loss: A retrospective review of 316 patients. J Am Acad Dermatol. 2020 Nov;83(5):1478-1479. doi: 10.1016/j.jaad.2020.03.034. Epub 2020 Mar 22. No abstract available. — View Citation

Kumarendran B, O'Reilly MW, Manolopoulos KN, Toulis KA, Gokhale KM, Sitch AJ, Wijeyaratne CN, Coomarasamy A, Arlt W, Nirantharakumar K. Polycystic ovary syndrome, androgen excess, and the risk of nonalcoholic fatty liver disease in women: A longitudinal study based on a United Kingdom primary care database. PLoS Med. 2018 Mar 28;15(3):e1002542. doi: 10.1371/journal.pmed.1002542. eCollection 2018 Mar. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
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)	Baseline and 6 months
Secondary	Change in hepatic steatosis by Magnetic Resonance Proton Density Fat Fraction (PDFF)	The investigators will assess for percent change in fat fraction by MRI-PDFF	Baseline and 6 months
Secondary	Change in visceral adipose tissue (VAT) volume by Magnetic Resonance Imaging (MRI)	The investigators will assess for percent change in VAT as quantified by MRI	Baseline and 6 months
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	Baseline and 6 months
Secondary	Change in the NAFLD Activity Score (NAS) on a scale from 0 (low activity) to 8 (high activity)	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).	Baseline and 6 months