Saroglitazar Magnesium for the Treatment of Nonalcoholic Steatohepatitis With Fibrosis

Nonalcoholic Steatohepatitis Clinical Trial

— NASH  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05011305
• Other study ID #: SARO.20.002
• Status: Recruiting
• Phase: Phase 2
• Start date: August 18, 2021
• Est. completion date: July 2025

Study information

• Verified date: December 2023
• Source: Zydus Therapeutics Inc.
• Contact: Farheen Shaikh
• Phone: +1 6094534751
• Email: fshaikh[@]zydustherapeutics.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Saroglitazar Magnesium for the Treatment of Nonalcoholic Steatohepatitis

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 information / eligibility

• Status: Recruiting
• Enrollment: 240
• Est. completion date: July 2025
• Est. primary completion date: July 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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:

1. 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)

2. Primary biliary cholangitis (PBC)

3. Primary sclerosing cholangitis (PSC)

4. Definite autoimmune liver disease or overlap syndrome

5. Alcoholic liver disease

6. Hemochromatosis

7. Wilsons disease

8. 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:

1. 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.

2. 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.

3. Immune modulatory agents including anti-TNF-a 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.

4. 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.

5. 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:

1. 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;

2. 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.

3. history of unstable cardiac dysrhythmias

4. uncontrolled hypertension at screening

5. 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:

1. Hemoglobin <9 g/dL

2. WBC count <2.5 × 103/µL

3. Neutrophil count <1.5 × 103/µL

4. Platelets <140 × 103/µL

5. INR = 1.3 (in the absence of anticoagulants)

6. Total bilirubin > ULN except in Gilbert's syndrome. In subjects with known Gilbert's syndrome, direct bilirubin > 2 x ULN

7. Albumin <3.5 g/dL

8. eGFR <60 mL/min/1.73 m2

9. ALP = 2x ULN

10. 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:

1. Pregnant/lactating female (including positive pregnancy test at screening)

2. 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.

Related Conditions & MeSH terms

• Fatty Liver
• Fibrosis
• Non-alcoholic Fatty Liver Disease
• Nonalcoholic Steatohepatitis

Intervention

Drug:
• Saroglitazar Magnesium 2 mg
Patients randomly assigned to this group will receive Saroglitazar Magnesium 2 mg tablet orally once daily in the morning before breakfast without food, for the duration of treatment.
• Saroglitazar Magnesium 4 mg
Patients randomly assigned to this group will receive Saroglitazar Magnesium 4 mg tablet orally once daily in the morning before breakfast without food, for the duration of treatment.
• Placebo
Patients randomly assigned to this group will receive Placebo tablet orally once daily in the morning before breakfast without food, for the duration of treatment.

Locations

Country	Name	City	State
Argentina	Zydus AR001	Caba
Argentina	Zydus AR003	Caba
Argentina	Zydus AR005	Caba
Argentina	Zydus AR006	Caba
Argentina	Zydus AR007	Caba
Argentina	Zydus AR008	Caba
Argentina	Zydus AR012	Caba
Argentina	Zydus AR013	Caba
Argentina	Zydus AR009	Mar Del Plata
Argentina	Zydus AR011	Mar Del Plata
Argentina	Zydus AR002	Ramos Mejía
Argentina	Zydus AR010	Rosario
Argentina	Zydus AR004	Salta
Turkey	Zydus TR003	Adana
Turkey	Zydus TR001	Ankara
Turkey	Zydus TR002	Ankara
Turkey	Zydus TR004	Bursa
Turkey	Zydus TR005	Gaziantep
Turkey	Zydus TR008	Istanbul
Turkey	Zydus TR009	Istanbul
Turkey	Zydus TR006	Izmir
Turkey	Zydus TR007	Izmir
Turkey	Zydus TR011	Kayseri
Turkey	Zydus TR010	Kocaeli
Turkey	Zydus TR012	Mersin
Turkey	Zydus TR013	Rize
Turkey	Zydus TR014	Trabzon
United States	Zydus US002	Arlington	Texas
United States	Zydus US018	Asheville	North Carolina
United States	Zydus US039	Aurora	Colorado
United States	Zydus US051	Austin	Texas
United States	Zydus US032	Birmingham	Alabama
United States	Zydus US017	Boston	Massachusetts
United States	Zydus US015	Charleston	South Carolina
United States	Zydus US030	Charleston	South Carolina
United States	Zydus US027	Charlotte	North Carolina
United States	Zydus US009	Cincinnati	Ohio
United States	Zydus US010	Cincinnati	Ohio
United States	Zydus US035	Cleveland	Ohio
United States	Zydus US073	Columbia	South Carolina
United States	Zydus US074	Columbia	Missouri
United States	Zydus US106	Edinburg	Texas
United States	Zydus US057	Fort Myers	Florida
United States	Zydus US061	Fort Worth	Texas
United States	Zydus US011	Hermitage	Tennessee
United States	Zydus US060	Hershey	Pennsylvania
United States	Zydus US079	Homewood	Alabama
United States	Zydus US071	Houma	Louisiana
United States	Zydus US067	Houston	Texas
United States	Zydus US013	Huntington Park	California
United States	Zydus US020	Indianapolis	Indiana
United States	Zydus US065	La Jolla	California
United States	Zydus US003	Lakeland	Florida
United States	Zydus US016	Lakewood Ranch	Florida
United States	Zydus US080	Long Beach	California
United States	Zydus US022	Los Angeles	California
United States	Zydus US062	Los Angeles	California
United States	Zydus US070	Manassas	Virginia
United States	Zydus US069	Manhasset	New York
United States	Zydus US014	Marrero	Louisiana
United States	Zydus US034	Miami	Florida
United States	Zydus US038	Miami	Florida
United States	Zydus US054	Miami	Florida
United States	Zydus US023	Murrieta	California
United States	Zydus US028	Nashville	Tennessee
United States	Zydus US066	New York	New York
United States	Zydus US081	Ocala	Florida
United States	Zydus US052	Orange	California
United States	Zydus US012	Panorama City	California
United States	Zydus US053	Philadelphia	Pennsylvania
United States	Zydus US047	Phoenix	Arizona
United States	Zydus US021	Richmond	Virginia
United States	Zydus US082	Richmond	Virginia
United States	Zydus US031	San Antonio	Texas
United States	Zydus US036	San Antonio	Texas
United States	Zydus US043	San Antonio	Texas
United States	Zydus US102	San Antonio	Texas
United States	Zydus US103	San Antonio	Texas
United States	Zydus US077	Sparta	New Jersey
United States	Zydus US072	Springboro	Ohio
United States	Zydus US025	Tucson	Arizona
United States	Zydus US078	Waco	Texas
United States	Zydus US076	Wichita Falls	Texas
United States	Zydus US004	Winter Park	Florida
United States	Zydus US019	Wyoming	Michigan

Sponsors (1)

Lead Sponsor	Collaborator
Zydus Therapeutics Inc.

Countries where clinical trial is conducted

United States,  Argentina,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Resolution of steatohepatitis with no worsening of fibrosis	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	52 Weeks/EOT
Secondary	Improvement in liver fibrosis with no increase in NAS for ballooning, inflammation or steatosis	Proportion of subjects achieving improvement in liver fibrosis (reduction of at least one stage) with no increase in NAS for ballooning, inflammation or steatosis	Week 52/EOT
Secondary	2 points improvement in NAS	Proportion of subjects with at least 2 points improvement in NAS at Week 76/EOT with at least 1-point improvement in either ballooning or inflammation and no worsening of liver fibrosis	Week 52/EOT
Secondary	Improvement in steatosis, ballooning, inflammation and fibrosis from liver biopsy	Proportion of subjects with =1 point improvement in steatosis, ballooning, inflammation and fibrosis	Week 52/EOT
Secondary	Decrease in SAF score on liver biopsy	Proportion of subjects with decrease in SAF score =2 combining hepatocellular inflammation and ballooning without worsening of fibrosis	Week 52/EOT
Secondary	Histological score changes in steatosis, ballooning, inflammation, and fibrosis	Change from baseline in steatosis, ballooning, inflammation, and fibrosis	Week 52/EOT
Secondary	Change in liver enzyme parameters including (ALT, AST, ALP, GGT, total bilirubin, albumin)	Change from baseline in liver enzyme parameters (ALT, AST, ALP, GGT, total bilirubin, albumin)	Week 52/EOT
Secondary	Change in non-invasive markers of steatosis	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)	Week 52/EOT
Secondary	Change in n lipid parameters including (TG, LDLC, TC, HDL-C, non-HDL-C, VLDL-C	Change from baseline in lipid parameters (TG, LDLC, TC, HDL-C, non-HDL-C, VLDL-C)	Week 52/EOT
Secondary	Change in body weight (any change from baseline)	Change from baseline in body weight	Week 52/EOT
Secondary	Change in insulin resistance marker, HOMA-IR	Change from baseline in insulin resistance marker (HOMA-IR)	Week 52/EOT
Secondary	Change in inflammatory markers including (CK-18 [M30], IL-6, CRP)	Change from baseline in inflammatory markers (CK-18 [M30], IL-6, CRP)	Week 52/EOT
Secondary	Change in glucose homeostasis markers including (HbA1c, FPG)	Change from baseline in glucose homeostasis markers (HbA1c, FPG)	Week 52/EOT