Saroglitazar Magnesium for the Treatment of Nonalcoholic Steatohepatitis With Fibrosis
- Conditions
- Nonalcoholic SteatohepatitisFibrosis
- Interventions
- Registration Number
- NCT05011305
- Lead Sponsor
- Zydus Therapeutics Inc.
- Brief Summary
Saroglitazar Magnesium for the Treatment of Nonalcoholic Steatohepatitis
- Detailed Description
A Phase 2b, Prospective, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate Efficacy and Safety of Saroglitazar Magnesium in Subjects with Nonalcoholic Steatohepatitis and Fibrosis.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 240
- Males or females, between 18 and 75 years of age, both inclusive at screening.
- BMI ≤45 kg/m²
- Histological confirmation of NASH with liver fibrosis by central pathologist on a diagnostic liver biopsy with a NAS ≥5 with at least one-point score in each of the three components of the NAFLD activity score [NAS] (steatosis scored 0-3, ballooning degeneration scored 0-2, and lobular inflammation scored 0-3) and NASH by pattern recognition Note: The biopsy must not have been performed more than 24 weeks before randomization.
- The subjects must have a stable body weight (no more than 5% change) between the time of biopsy and randomization.
- Fibrosis stage 2 and 3, according to the NASH CRN fibrosis staging, reported by central pathologist.
- If the subjects have type 2 diabetes mellitus, then it must be moderately controlled with HbA1c ≤ 9% and on a stable dose of permitted anti-diabetic medication for at least 90 days before screening until randomization.
- If the subjects are taking vitamin E > 400 IU/day, then it must be on a stable dose for at least 24 weeks prior to screening or, if a historical biopsy is used, at least 24 weeks prior to baseline liver biopsy until randomization.
- Must provide written informed consent and agree to comply with the trial protocol.
-
Consumption of >3 units of alcohol per day (>21 units per week) if male and >2 units of alcohol per day (>14 units per week) if female for at least 12 consecutive weeks within 5 years before screening (Note: 1 unit = 12 ounces of beer, 4 ounces of wine or 1 ounce of spirits/hard liquor)
-
History or presence of other concomitant liver diseases at screening:
- Chronic hepatitis B (HBV) or hepatitis C virus (HCV) infection (However, If the subject has been treated for the HCV infection and has been cured at least 5 years from screening, such subjects can be enrolled in the study)
- Primary biliary cholangitis (PBC)
- Primary sclerosing cholangitis (PSC)
- Definite autoimmune liver disease or overlap syndrome
- Alcoholic liver disease
- Hemochromatosis
- Wilsons disease
- Alpha-1 antitrypsin deficiency
-
Subject with known cirrhosis, either based on histology, clinical criteria or any non-invasive diagnostic modality, within 24 weeks prior to the randomization.
-
Evidence of portal hypertension (low platelet count, esophageal varices, ascites, history of hepatic encephalopathy, splenomegaly) at screening.
-
Treatment with glucagon-like peptide-1 receptor agonists (GLP-1RAs), sodium glucose cotransporter- 2 (SGLT-2) inhibitors, and dipeptidyl peptidase 4 inhibitors (gliptins) unless stable for 90 days prior to screening or, if a historical biopsy is used, from 90 days prior to baseline liver biopsy until randomization.
-
Use of concurrent medications prior to screening including:
- Anti-NASH therapy(s) including S-adenosyl methionine (SAMe), ursodeoxycholic acid (UDCA), obeticholic acid and milk thistle in the period from 90 days prior to screening or, if a historical biopsy is used, from 90 days prior to baseline liver biopsy until randomization.
- Antidiabetic mediation which may impact NASH histology including thiazolidinediones (pioglitazone, rosiglitazone) in the period from 90 days prior to screening or, if a historical biopsy is used, from 90 days prior to baseline liver biopsy until randomization.
- Immune modulatory agents including anti-TNF-α therapies (infliximab, adalimumab, etanercept) or anti-integrin therapy (namixilab) in the period from 28 days prior to screening or if a historical biopsy is used from 28 days prior to baseline liver biopsy until randomization.
- Any treatment or anticipated initiation (intended use for more than 14 consecutive days) of medications known to have an effect on steatosis (e.g. treatment with corticosteroids [topical and inhaled are allowed]), methotrexate, tamoxifen, valproic acid, amiodarone or tetracycline, estrogens in doses higher than used in oral contraceptives, vitamin A, L-asparaginase, valproate, chloroquine, or antiretroviral drugs in the period from 28 days prior to screening or, if a historical biopsy is used, from 28 days prior to baseline liver biopsy until randomization.
- Treatment with orlistat, zonisamide, topiramate, phentermine, lorcaserin, bupropion, or naltrexone alone, or in combination or any other medication, that could promote weight loss, in the opinion of the investigator, in the period from 28 days prior to screening or if a historical biopsy is used from 28 days prior to baseline liver biopsy until randomization.
-
Changing doses of statins (simvastatin, pitavastatin, pravastatin, atorvastatin, fluvastatin, lovastatin, rosuvastatin) or fibrates (clofibrate, Fenofibrate) in the 90 days preceding screening until randomization.
-
Use of drugs that are known CYP2C8 inhibitors/substrate in the 28 days preceding screening until randomization.
-
History of liver transplant
-
Any weight reduction surgery in the 2 years prior to screening or planned during the study (weight reduction surgery is disallowed during the study), and malabsorptive weight loss surgery (Rouxen-Y or distal gastric bypass) at any time prior to screening.
Note: Lap banding, if the band has been removed >6 months before baseline liver biopsy, or intragastric balloon, if the balloon has been removed > 6 months before baseline liver biopsy, is allowed.
-
Type 1 diabetes mellitus
-
History of stomach or intestinal surgery or resection within the six months prior to screening that would potentially alter absorption and/or excretion of orally administered drugs as judged by the investigator.
-
Unstable cardiovascular disease, including:
- unstable angina, (i.e., new or worsening symptoms of coronary heart disease) in the 90 days before screening and throughout the screening period; acute coronary syndrome in the 24 weeks before screening and throughout the screening period;
- acute myocardial infarction in the 90 days before screening and throughout the screening period; or heart failure of New York Heart Association class (III - IV), worsening congestive heart failure, or coronary artery intervention, in the 24 weeks before screening and throughout the screening period.
- history of unstable cardiac dysrhythmias
- uncontrolled hypertension at screening
- stroke or transient ischemic attack in the 24 weeks before screening
-
History of myopathies or evidence of active muscle disease demonstrated by CPK ≥ 5 times ULN at screening.
-
Subjects whose ALT, AST, or ALP exceeds by more than 50% at Visit 2 reading compared to Visit 1.
Note: If the ALT, AST or ALP values at Visit 2 exceed by more than 50% from Visit 1, then a third value will be measured to assess for the trend. If the third value shows continued increase ≥ 10%, then subject is considered ineligible for randomization.
-
Any of the following laboratory values at screening:
- Hemoglobin <9 g/dL
- WBC count <2.5 × 103/µL
- Neutrophil count <1.5 × 103/µL
- Platelets <140 × 103/µL
- INR ≥ 1.3 (in the absence of anticoagulants)
- Total bilirubin > ULN except in Gilbert's syndrome. In subjects with known Gilbert's syndrome, direct bilirubin > 2 x ULN
- Albumin <3.5 g/dL
- eGFR <60 mL/min/1.73 m2
- ALP ≥ 2x ULN
- ALT or AST ≥ 250 U/L
-
Participation in any other therapeutic clinical study and on active treatment in the past 90 days of the screening.
-
History of benign or malignant bladder tumors, and/or hematuria or has current hematuria except due to a urinary tract infection.
-
History of malignancy in the past 5 years and/or active neoplasm with the exception of resolved superficial nonmelanoma skin cancer.
-
Known allergy, sensitivity or intolerance to the study drug, comparator or formulation ingredients.
-
Pregnancy-related exclusions, including:
- Pregnant/lactating female (including positive pregnancy test at screening)
- Fertile women and men, UNLESS using effective contraceptive methods (such as an intrauterine device or other mechanical contraception method with condom or diaphragm and spermicide or proper use of hormonal contraceptives that inhibit ovulation) throughout the study. For male subjects, contraception measures (condom and spermicide) must be taken during the study, either by the male participant or his female partner.
(Note: Enrolled females otherwise must be surgically sterilized for at least 24 weeks before screening; postmenopausal, defined as 52 weeks with no menses without an alternative medical cause; or following sexual abstinence.)
- History or other evidence of severe illness or any other conditions that would make the subject, in the opinion of the investigator, unsuitable for the study (such as poorly controlled psychiatric disease, HIV, coronary artery disease or active gastrointestinal conditions that might interfere with drug absorption)
- Receiving an elemental diet or parenteral nutrition.
- Chronic pancreatitis or pancreatic insufficiency.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Saroglitazar Magnesium 4 mg Saroglitazar Magnesium 4 mg Saroglitazar Magnesium 4 mg tablet orally administered once daily in the morning before breakfast without food, for the duration of treatment. Placebo Placebo Placebo tablet orally administered once daily in the morning before breakfast without food, for the duration of treatment. Saroglitazar Magnesium 2 mg Saroglitazar Magnesium 2 mg Saroglitazar Magnesium 2 mg tablet orally administered once daily in the morning before breakfast without food, for the duration of treatment.
- Primary Outcome Measures
Name Time Method Resolution of steatohepatitis with no worsening of fibrosis 52 Weeks/EOT Resolution of steatohepatitis is defined as absent fatty liver disease or isolated or simple steatosis without steatohepatitis and a NAS of 0-1 for inflammation, 0 for ballooning, and any value for Steatosis
- Secondary Outcome Measures
Name Time Method Improvement in liver fibrosis with no increase in NAS for ballooning, inflammation or steatosis Week 52/EOT Proportion of subjects achieving improvement in liver fibrosis (reduction of at least one stage) with no increase in NAS for ballooning, inflammation or steatosis
2 points improvement in NAS Week 52/EOT Proportion of subjects with at least 2 points improvement in NAS at Week 52/EOT with at least 1-point improvement in either ballooning or inflammation and no worsening of liver fibrosis
Improvement in steatosis, ballooning, inflammation and fibrosis from liver biopsy Week 52/EOT Proportion of subjects with ≥1 point improvement in steatosis, ballooning, inflammation and fibrosis
Decrease in SAF score on liver biopsy Week 52/EOT Proportion of subjects with decrease in SAF score ≥2 combining hepatocellular inflammation and ballooning without worsening of fibrosis
Histological score changes in steatosis, ballooning, inflammation, and fibrosis Week 52/EOT Change from baseline in steatosis, ballooning, inflammation, and fibrosis
Change in liver enzyme parameters including (ALT, AST, ALP, GGT, total bilirubin, albumin) Week 52/EOT Change from baseline in liver enzyme parameters (ALT, AST, ALP, GGT, total bilirubin, albumin)
Change in non-invasive markers of steatosis Week 52/EOT Change from baseline in non-invasive markers of steatosis (Enhanced Liver Fibrosis \[ELF\] test, Fibrosis 4 \[FIB 4\], APRI \[AST to Platelet Ratio Index\], NFS \[NAFLD Fibrosis Score\], PRO-C3)
Change in n lipid parameters including (TG, LDLC, TC, HDL-C, non-HDL-C, VLDL-C Week 52/EOT Change from baseline in lipid parameters (TG, LDLC, TC, HDL-C, non-HDL-C, VLDL-C)
Change in body weight (any change from baseline) Week 52/EOT Change from baseline in body weight
Change in insulin resistance marker, HOMA-IR Week 52/EOT Change from baseline in insulin resistance marker (HOMA-IR)
Change in inflammatory markers including (CK-18 [M30], IL-6, CRP) Week 52/EOT Change from baseline in inflammatory markers (CK-18 \[M30\], IL-6, CRP)
Change in glucose homeostasis markers including (HbA1c, FPG) Week 52/EOT Change from baseline in glucose homeostasis markers (HbA1c, FPG)
Trial Locations
- Locations (152)
Zydus US090
🇺🇸Long Beach, California, United States
Zydus US040
🇺🇸Los Angeles, California, United States
Zydus US059
🇺🇸Rancho Cucamonga, California, United States
Zydus US026
🇺🇸Chandler, Arizona, United States
Zydus US050
🇺🇸Phoenix, Arizona, United States
Zydus US087
🇺🇸Tucson, Arizona, United States
Zydus US029
🇺🇸Tucson, Arizona, United States
Zydus US046
🇺🇸Little Rock, Arkansas, United States
Zydus US118
🇺🇸Chula Vista, California, United States
Zydus US041
🇺🇸Fresno, California, United States
Zydus US111
🇺🇸Gardena, California, United States
Zydus US094
🇺🇸Lancaster, California, United States
Zydus US037
🇺🇸Redwood City, California, United States
Zydus US006
🇺🇸Aventura, Florida, United States
Zydus US122
🇺🇸Clearwater, Florida, United States
Zydus US108
🇺🇸Hallandale Beach, Florida, United States
Zydus US096
🇺🇸Hialeah Gardens, Florida, United States
Zydus US125
🇺🇸Largo, Florida, United States
Zydus US001
🇺🇸Maitland, Florida, United States
Zydus US124
🇺🇸Maitland, Florida, United States
Zydus US098
🇺🇸Miami Lakes, Florida, United States
Zydus US007
🇺🇸Miami, Florida, United States
Zydus US024
🇺🇸Miami, Florida, United States
Zydus US121
🇺🇸Miami, Florida, United States
Zydus US099
🇺🇸Naples, Florida, United States
Zydus US085
🇺🇸Orlando, Florida, United States
Zydus US104
🇺🇸Port Orange, Florida, United States
Zydus US113
🇺🇸Gainesville, Georgia, United States
Zydus US107
🇺🇸Dalton, Georgia, United States
Zydus US114
🇺🇸Marietta, Georgia, United States
Zydus US119
🇺🇸Savannah, Georgia, United States
Zydus US100
🇺🇸West Des Moines, Iowa, United States
Zydus US049
🇺🇸Kansas City, Kansas, United States
Zydus US045
🇺🇸New Orleans, Louisiana, United States
Zydus US123
🇺🇸West Monroe, Louisiana, United States
Zydus US042
🇺🇸Bethesda, Maryland, United States
Zydus US086
🇺🇸Burlington, Massachusetts, United States
Zydus US092
🇺🇸Chesterfield, Michigan, United States
Zydus US115
🇺🇸St. Paul, Minnesota, United States
Zydus US120
🇺🇸Kansas City, Missouri, United States
Zydus US063
🇺🇸St. Louis, Missouri, United States
Zydus US084
🇺🇸St. Louis, Missouri, United States
Zydus US116
🇺🇸Reno, Nevada, United States
Zydus US083
🇺🇸Albany, New York, United States
Zydus US055
🇺🇸New York, New York, United States
Zydus US068
🇺🇸Rochester, New York, United States
Zydus US056
🇺🇸Staten Island, New York, United States
Zydus US091
🇺🇸Columbus, Ohio, United States
Zydus US093
🇺🇸Westlake, Ohio, United States
Zydus US075
🇺🇸Greenwood, South Carolina, United States
Zydus US112
🇺🇸Summerville, South Carolina, United States
Zydus US064
🇺🇸Austin, Texas, United States
Zydus US101
🇺🇸Austin, Texas, United States
Zydus US089
🇺🇸Bellaire, Texas, United States
Zydus US105
🇺🇸Brownsville, Texas, United States
Zydus US048
🇺🇸Dallas, Texas, United States
Zydus US095
🇺🇸Edinburg, Texas, United States
Zydus US109
🇺🇸Houston, Texas, United States
Zydus US005
🇺🇸Houston, Texas, United States
Zydus US110
🇺🇸Houston, Texas, United States
Zydus US117
🇺🇸Katy, Texas, United States
Zydus US008
🇺🇸San Antonio, Texas, United States
Zydus US058
🇺🇸Waco, Texas, United States
Zydus US088
🇺🇸Ogden, Utah, United States
Zydus US044
🇺🇸Seattle, Washington, United States
Zydus US033
🇺🇸Seattle, Washington, United States
Zydus US097
🇵🇷San Juan, Puerto Rico
Zydus US032
🇺🇸Birmingham, Alabama, United States
Zydus US079
🇺🇸Homewood, Alabama, United States
Zydus US047
🇺🇸Phoenix, Arizona, United States
Zydus US025
🇺🇸Tucson, Arizona, United States
Zydus US013
🇺🇸Huntington Park, California, United States
Zydus US065
🇺🇸La Jolla, California, United States
Zydus US080
🇺🇸Long Beach, California, United States
Zydus US022
🇺🇸Los Angeles, California, United States
Zydus US062
🇺🇸Los Angeles, California, United States
Zydus US023
🇺🇸Murrieta, California, United States
Zydus US052
🇺🇸Orange, California, United States
Zydus US012
🇺🇸Panorama City, California, United States
Zydus US039
🇺🇸Aurora, Colorado, United States
Zydus US057
🇺🇸Fort Myers, Florida, United States
Zydus US003
🇺🇸Lakeland, Florida, United States
Zydus US016
🇺🇸Lakewood Ranch, Florida, United States
Zydus US034
🇺🇸Miami, Florida, United States
Zydus US038
🇺🇸Miami, Florida, United States
Zydus US054
🇺🇸Miami, Florida, United States
Zydus US081
🇺🇸Ocala, Florida, United States
Zydus US004
🇺🇸Winter Park, Florida, United States
Zydus US020
🇺🇸Indianapolis, Indiana, United States
Zydus US071
🇺🇸Houma, Louisiana, United States
Zydus US014
🇺🇸Marrero, Louisiana, United States
Zydus US017
🇺🇸Boston, Massachusetts, United States
Zydus US019
🇺🇸Wyoming, Michigan, United States
Zydus US074
🇺🇸Columbia, Missouri, United States
Zydus US077
🇺🇸Sparta, New Jersey, United States
Zydus US069
🇺🇸Manhasset, New York, United States
Zydus US018
🇺🇸Asheville, North Carolina, United States
Zydus US027
🇺🇸Charlotte, North Carolina, United States
Zydus US066
🇺🇸New York, New York, United States
Zydus US010
🇺🇸Cincinnati, Ohio, United States
Zydus US009
🇺🇸Cincinnati, Ohio, United States
Zydus US035
🇺🇸Cleveland, Ohio, United States
Zydus US072
🇺🇸Springboro, Ohio, United States
Zydus US060
🇺🇸Hershey, Pennsylvania, United States
Zydus US053
🇺🇸Philadelphia, Pennsylvania, United States
Zydus US073
🇺🇸Columbia, South Carolina, United States
Zydus US011
🇺🇸Hermitage, Tennessee, United States
Zydus US028
🇺🇸Nashville, Tennessee, United States
Zydus US015
🇺🇸Charleston, South Carolina, United States
Zydus US030
🇺🇸Charleston, South Carolina, United States
Zydus US002
🇺🇸Arlington, Texas, United States
Zydus US051
🇺🇸Austin, Texas, United States
Zydus US106
🇺🇸Edinburg, Texas, United States
Zydus TR011
🇹🇷Kayseri, Turkey
Zydus US061
🇺🇸Fort Worth, Texas, United States
Zydus US067
🇺🇸Houston, Texas, United States
Zydus US031
🇺🇸San Antonio, Texas, United States
Zydus US103
🇺🇸San Antonio, Texas, United States
Zydus US036
🇺🇸San Antonio, Texas, United States
Zydus US102
🇺🇸San Antonio, Texas, United States
Zydus US043
🇺🇸San Antonio, Texas, United States
Zydus US078
🇺🇸Waco, Texas, United States
Zydus US076
🇺🇸Wichita Falls, Texas, United States
Zydus US070
🇺🇸Manassas, Virginia, United States
Zydus US082
🇺🇸Richmond, Virginia, United States
Zydus US021
🇺🇸Richmond, Virginia, United States
Zydus TR010
🇹🇷Kocaeli, Turkey
Zydus AR004
🇦🇷Buenos Aires, Argentina
Zydus AR001
🇦🇷Caba, Argentina
Zydus AR013
🇦🇷Caba, Argentina
Zydus AR007
🇦🇷Caba, Argentina
Zydus AR006
🇦🇷Caba, Argentina
Zydus AR005
🇦🇷Caba, Argentina
Zydus AR008
🇦🇷Caba, Argentina
Zydus AR012
🇦🇷Caba, Argentina
Zydus AR003
🇦🇷Caba, Argentina
Zydus AR009
🇦🇷Mar Del Plata, Argentina
Zydus AR011
🇦🇷Mar Del Plata, Argentina
Zydus AR002
🇦🇷Ramos Mejía, Argentina
Zydus AR010
🇦🇷Rosario, Argentina
Zydus TR003
🇹🇷Adana, Turkey
Zydus TR002
🇹🇷Ankara, Turkey
Zydus TR001
🇹🇷Ankara, Turkey
Zydus TR004
🇹🇷Bursa, Turkey
Zydus TR005
🇹🇷Gaziantep, Turkey
Zydus TR009
🇹🇷Istanbul, Turkey
Zydus TR008
🇹🇷Istanbul, Turkey
Zydus TR007
🇹🇷İzmir, Turkey
Zydus TR006
🇹🇷İzmir, Turkey
Zydus TR012
🇹🇷Mersin, Turkey
Zydus TR013
🇹🇷Rize, Turkey
Zydus TR014
🇹🇷Trabzon, Turkey