Saroglitazar Magnesium 4 mg in the Treatment of Nonalcoholic Fatty Liver Disease (NAFLD) in Women With PCOS (EVIDENCES VII)

Phase 2TerminatedNCT03617263

Zydus Therapeutics Inc.60 enrolled

Overview

This is a multicenter, phase 2A, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of Saroglitazar Magnesium in women with well characterized PCOS.

This is a multicenter, phase 2A, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of Saroglitazar Magnesium in women with well characterized PCOS. The study will be conducted over a period of up to 34 weeks and will include Screening (Days -28 to -7) Phase, a 24-week Treatment Phase following randomization on Day 1. The primary endpoint of the study is change in hepatic fat content from baseline following 24 weeks of treatment as measured by MRI-PDFF.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

Non-alcoholic Fatty Liver Disease in Women With PCOS

Interventions

Saroglitazar Magnesium 4 mg TabletDRUG

Patients randomly assigned to this group will receive Saroglitazar Magnesium orally once daily for 24 weeks.

PlaceboDRUG

Patients randomly assigned to this group will receive Placebo tablet orally once daily for 24 weeks.

Eligibility

Sex: FEMALEMin age: 18 YearsMax age: 45 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Females, 18 to 45 years of age. * Previously confirmed diagnosis of PCOS: 1. oligo-and/or anovulation; 2. hyperandrogenism (clinical and/or biochemical); 3. polycystic ovary morphology on ultrasonography * Evidence of NAFLD within 6 months prior to the Screening Visit (Visit 1). * Alanine transaminase ≥ 38 U/L at Visit 1. Visit 2 ALT must not increase \>30% from Visit 1. * Hepatic fat fraction ≥10% by MRI-PDFF. * Willingness to participate in the study. * Ability to understand and give informed consent for participation. * Woman who agrees to use the contraceptive methods. Exclusion Criteria: * Presence of other chronic liver diseases (hepatitis B or C, autoimmune hepatitis, cholestatic liver disease, Wilsons disease, hemochromatosis, etc.). * Average alcohol consumption ≥ 7 drinks per week for women in the 6 months prior to enrollment. * Clinical, imaging, or histological evidence of cirrhosis. * Patients who have used medications known to cause hepatic steatosis for more than 2 weeks in the past year. * Prior bariatric surgery. * Weight loss of more than 5% in the 3 months preceding screening. * Severe co-morbidities (e.g., advanced cardiac, renal, pulmonary, or psychiatric illness). * Known allergy, sensitivity or intolerance to Saroglitazar Magnesium, comparator or formulation ingredients. * Use of antidiabetic and lipid lowering medications if the dose is not stable for at least the 3 months preceding screening. * Intake of Vitamin E (\>100 IU/day) or multivitamins containing Vitamin E (\>100 IU/day) 3 months before enrollment. * Use of drugs with potential effect on NAFLD/NASH in the 3 months prior to screening. * Illicit substance abuse within the past 12 months. * Pregnant or breast feeding females. * Women with known Cushing syndrome or hyperprolactinemia. * Refusal or inability to comply with the requirements of the protocol, for any reason, including scheduled clinic visits and laboratory tests. * History of myopathies or evidence of active muscle diseases. * History or current significant cardiovascular disease. * History of malignancy. * History of bladder disease.

Locations (19)

Zydus US005

Chandler, Arizona, United States

Zydus US004

Panorama City, California, United States

Outcomes

Primary Outcomes

Hepatic Fat Content

Change in hepatic fat content from baseline following 24 weeks of treatment as measured by Magnetic Resonance Imaging-derived Proton Density-fat Fraction (MRI-PDFF)

Time frame: Baseline and Week 24

Secondary Outcomes

Liver Enzymes/Liver Function Tests

Changes from baseline to week 12 and week 24 in Alkaline phosphatase

Time frame: Baseline, Week 12, and Week 24

Liver Enzymes/Liver Function Tests

Changes from baseline to week 12 and week 24 in Alanine aminotransferase

Time frame: Baseline, Week 12, and Week 24

Liver Enzymes/Liver Function Tests

Changes from baseline to week 12 and week 24 in Aspartate Aminotransferase

Time frame: Baseline, Week 12, and Week 24

Liver Enzymes/Liver Function Tests

Changes from baseline to week 12 and week 24 in gamma-glutamyl transferase

Time frame: Baseline, Week 12, and Week 24

Liver Enzymes/Liver Function Tests

Changes from baseline to week 12 and week 24 in serum protein

Time frame: Baseline, Week 12, and Week 24

Liver Enzymes/Liver Function Tests

Changes from baseline to week 12 and week 24 in albumin

Time frame: Baseline, Week 12, and Week 24

Liver Enzymes/Liver Function Tests

Changes from baseline to week 12 and week 24 in total bilirubin.

Data from ClinicalTrials.gov

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Zydus US002

San Francisco, California, United States

Zydus US008

Aurora, Colorado, United States

Zydus US010

Miami, Florida, United States

Zydus US001

Indianapolis, Indiana, United States

Zydus US011

Morehead City, North Carolina, United States

Zydus US003

Marion, Ohio, United States

Zydus US015

Hershey, Pennsylvania, United States

Zydus US014

Philadelphia, Pennsylvania, United States

...and 9 more locations

Time frame: Baseline, Week 12, and Week 24

Insulin Resistance

Evaluation of HOMA of Insulin Resistance Index determines insulin resistance and estimates insulin sensitivity, calculated by fasting insulin (μU/mL) multiplied by fasting glucose (mg/dL), and divided by a constant (405). A higher score indicates higher insulin resistance

Time frame: Baseline, Week 12, and Week 24

Liver Injury

Changes from baseline to week 24 in Liver Injury, including Cytokeratin (CK)-18. CK18 \[M30\] and CK-18 \[M-65\] were measured as biomarkers of hepatocyte apoptosis. Both are important indicators for liver tissue conditions and effectively reflect hepatocyte damage. A negative change from baseline indicates a decrease in hepatocyte apoptosis or a decrease in hepatocyte damage.

Time frame: Baseline and Week 24

Liver Injury

Changes from baseline to week 24 in high-sensitivity C-reactive protein (hs-CRP)

Time frame: Baseline and Week 24

Liver Injury

Changes from baseline to week 24 in Tumor necrosis factor (TNFα)

Time frame: Baseline and Week 24

Liver Stiffness

Changes from baseline to week 24 in liver stiffness measured by transient elastography/FibroScan

Time frame: Baseline and Week 24

Controlled Attenuation Parameter

Changes from baseline to week 24 in controlled attenuation parameter measured by transient elastography/ FibroScan

Time frame: Baseline and Week 24

Body Mass Index (BMI)

Changes from baseline to week 12 and week 24 in Body mass index

Time frame: Baseline, Week 12, and Week 24

Waist Circumference

Changes from baseline to week 12 and week 24 in waist circumference

Time frame: Baseline, Week 12, and Week 24

Changes From Baseline to Week 24 in MRI-derived Measures of Total Liver Fat Index

MRI-derived measures of total liver fat index. Total liver volume: The total liver volume was calculated through a process requiring segmentation image analysis. Liver volume was calculated after complete segmentation by summing the liver surface area at each segmented slice and then multiplying this sum by individual slice thickness, in milliliters (mL). Total liver fat index: The total liver fat index (TLFI, units: % mL) took into consideration the volume of liver from which proton-density fat fraction was derived. It was calculated as the product of liver volume and the liver mean proton-density fat fraction across all liver segments.

Time frame: Baseline and Week 24

Changes From Baseline to Week 24 in MRI-derived Measures of Total Liver Volume

MRI-derived measures of total liver volume (Liver volume will be calculated after complete segmentation by summing the liver surface area at each segmented slice, and then multiplying this sum by individual slice thickness, in millilitres \[mL\])

Time frame: Baseline and Week 24

Lipid and Lipoprotein Levels

Changes from baseline to week 12 and week 24 in Triglyceride (TG)

Time frame: Baseline, Week 12, and Week 24

Lipid and Lipoprotein Levels

Changes from baseline to week 12 and week 24 in Total cholesterol (TC)

Time frame: Baseline, Week 12, and Week 24

Lipid and Lipoprotein Levels

Changes from baseline to week 12 and week 24 in High-density lipoprotein

Time frame: Baseline, Week 12, and Week 24

Lipid and Lipoprotein Levels

Changes from baseline to week 12 and week 24 in Low-density lipoprotein (LDL)

Time frame: Baseline, Week 12, and Week 24

Lipid and Lipoprotein Levels

Changes from baseline to week 12 and week 24 in Small dense low density lipoprotein (sdLDL)

Time frame: Baseline, Week 12, and Week 24

Lipid and Lipoprotein Levels

Changes from baseline to week 12 and week 24 in Very low density lipoprotein (VLDL)

Time frame: Baseline, Week 12, and Week 24

Lipid and Lipoprotein Levels

Changes from baseline apolipoprotein A

Time frame: Baseline, Week 12, and Week 24

Lipid and Lipoprotein Levels

Changes from baseline in apolipoprotein B

Time frame: Baseline, Week 12, and Week 24

Sex Hormone Binding Globulin (SHBG) Level

Changes from baseline in SHBG level

Time frame: Baseline, Week 12, and Week 24

Ovarian Function

Changes from baseline in 17-hydroxyprogesterone

Time frame: Baseline, Week 12, and Week 24

Ovarian Function

Changes from baseline in Total testosterone

Time frame: Baseline, Week 12, and Week 24

Ovarian Function

Changes from baseline in free testosterone

Time frame: Baseline, Week 12, and Week 24

Ovarian Function

Changes from baseline in follicle-stimulating hormone (FSH)

Time frame: Baseline, Week 12, and Week 24

Ovarian Function

Changes from baseline in luteinizing hormone (LH)

Time frame: Baseline, Week 12, and Week 24

Ovarian Function

Changes from baseline in LH-to-FSH ratio

Time frame: Baseline, Week 12, and Week 24

Ovarian Function

Changes from baseline in estradiol

Time frame: Baseline, Week 12, and Week 24

Changes From Baseline to Week 12 and Week 24 in Free Androgen Index

Free androgen index is a ratio used to determine abnormal androgen status in humans, measured by Total testosterone level divided by the sex hormone binding globulin (SHBG) level, and then multiplying by a constant, usually 100. A higher score indicates a worse outcome (more androgenic).

Time frame: Baseline, Week 12, and Week 24

Peak Plasma Concentration [Cmax] (For Single Dose)

Pharmacokinetics of Saroglitazar following first dose

Time frame: PK sampling timepoints: pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, and 24 hours post-dose of First dose (visit 3)

Time to Reach Peak Plasma Concentration [Tmax] (For Single Dose)

Pharmacokinetics of Saroglitazar following first dose

Time frame: PK sampling timepoints: pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, and 24 hours post-dose of First dose (visit 3)

Area Under Plasma Concentration vs. Time Curve Till the Last Time Point [AUC0-t] (For Single Dose)

Pharmacokinetics of Saroglitazar following first dose

Time frame: PK sampling timepoints: pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, and 24 hours post-dose of First dose (visit 3)

Area Under Plasma Concentration vs. Time Curve Extrapolated to the Infinity (AUC0-∞) After First Dose (For Single Dose)

Pharmacokinetics of Saroglitazar following first dose

Time frame: PK sampling timepoints: pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, and 24 hours post-dose of First dose (visit 3)

Area Under Plasma Concentration vs. Time Curve in a 24 h Dosing Interval (AUCtau) After First Dose (For Single Dose)

Pharmacokinetics of Saroglitazar following first dose

Time frame: PK sampling timepoints: pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, and 24 hours post-dose of First dose (visit 3)

Elimination Rate Constant [Kel] (For Single Dose)

Pharmacokinetics of Saroglitazar following first dose

Time frame: PK sampling timepoints: pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, and 24 hours post-dose of First dose (visit 3)

Elimination Half-life [tHalf] (For Single Dose)

Pharmacokinetics of Saroglitazar following first dose

Time frame: PK sampling timepoints: pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, and 24 hours post-dose of First dose (Visit 3)

Apparent Volume of Distribution [Vd/F] (For Single Dose)

Pharmacokinetics of Saroglitazar following first dose

Time frame: PK sampling timepoints: pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, and 24 hours post-dose of First dose (visit 3)

Apparent Clearance [CL/F] (For Single Dose)

Pharmacokinetics of Saroglitazar following first dose

Time frame: PK sampling timepoints: pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, and 24 hours post-dose of First dose (visit 3)

Peak Plasma Concentration [Cmax,ss] (For Multiple Dose)

Pharmacokinetics of Saroglitazar following last dose

Time frame: PK sampling timepoints: pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0,10.0, and 24 hours post-dose of Last dose (Visit 8)

Time to Reach Peak Plasma Concentration [Tmax,ss] (For Multiple Dose)

Pharmacokinetics of Saroglitazar following last dose

Time frame: PK sampling timepoints: pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, and 24 hours post-dose of Last dose (visit 8)

Area Under Plasma Concentration vs. Time Curve in a 24 h Dosing Interval (AUCtau) After Last Dose (For Multiple Dose)

Pharmacokinetics of Saroglitazar following last dose

Time frame: PK sampling timepoints: pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, and 24 hours post-dose of Last dose (visit 8)

Elimination Rate Constant [Kel,ss] (For Multiple Dose)

Pharmacokinetics of Saroglitazar following last dose

Time frame: PK sampling timepoints: pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, and 24 hours post-dose of Last dose (Visit 8)

Elimination Half-life [Thalf,ss] (For Multiple Dose)

Pharmacokinetics of Saroglitazar following last dose

Time frame: PK sampling timepoints: pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, and 24 hours post-dose of Last dose (visit 8)

Apparent Volume of Distribution [Vd/F,ss] (For Multiple Dose)

Pharmacokinetics of Saroglitazar following last dose

Time frame: PK sampling timepoints: pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, and 24 hours post-dose of Last dose (visit 8)

Apparent Clearance [CL/F,ss] (For Multiple Dose)

Pharmacokinetics of Saroglitazar following last dose

Time frame: PK sampling timepoints: pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, and 24 hours post-dose of Last dose (visit 8)

Minimal or Trough Plasma Concentration [Cmin] (For Multiple Dose)

Pharmacokinetics of Saroglitazar following last dose

Time frame: PK sampling timepoints: pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, and 24 hours post-dose of Last dose (visit 8)

Fluctuation Index (For Multiple Dose)

Pharmacokinetics of Saroglitazar following the last dose. It is calculated as (Cmax - Cmin) / Cavg. The value has been multiplied by 100, hence has been expressed in percentage unit; where Cmax is the Maximum measured plasma concentration at steady state, Cmin is Minimal or trough plasma concentration at steady state, and Cavg is Average concentration = AUCtau,ss /tau.

Time frame: PK sampling timepoints: pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, and 24 hours post-dose of Last dose (visit 8)

Accumulation Index Calculated as a Ratio of AUCtau (Last Dose)/AUCtau (First Dose) (For Multiple Dose)

Pharmacokinetics of Saroglitazar following last dose

Time frame: PK sampling timepoints: pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, and 24 hours post-dose of Last dose (visit 8)