Saroglitazar Magnesium for the Treatment of Nonalcoholic Steatohepatitis With Fibrosis

Study Overview
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Brief Summary
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Saroglitazar Magnesium for the Treatment of Nonalcoholic Steatohepatitis

Detailed Description
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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.

Official Title
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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

Conditions
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Nonalcoholic Steatohepatitis, Fibrosis

Intervention / Treatment
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* Drug: Saroglitazar Magnesium 2 mg
* Drug: Saroglitazar Magnesium 4 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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. 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 time of screening. 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: 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 time of screening. 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 time of screening. 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 time of screening. 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 time of screening. 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 time of screening. 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 time of screening. Changing doses of statins (simvastatin, pitavastatin, pravastatin, atorvastatin, fluvastatin, lovastatin, rosuvastatin) or fibrates (clofibrate, Fenofibrate) in the 90 days preceding screening. Use of drugs that are known CYP2C8 inhibitors/substrate in the 28 days preceding screening. 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 240 subjects randomized in a 1:1:1 ratio to Saroglitazar 2 mg, Saroglitazar 4 mg or Placebo.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Saroglitazar Magnesium 2 mg<br>Saroglitazar Magnesium 2 mg tablet orally administered once daily in the morning before breakfast without food, for the duration of treatment (76 weeks). | Drug: Saroglitazar Magnesium 2 mg<br>* 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 (76 weeks).<br>* Other names: Investigational Product;|
| Experimental: Saroglitazar Magnesium 4 mg<br>Saroglitazar Magnesium 4 mg tablet orally administered once daily in the morning before breakfast without food, for the duration of treatment (76 weeks). | Drug: Saroglitazar Magnesium 4 mg<br>* 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 (76 weeks).<br>* Other names: Investigational Product;|
| Placebo Comparator: Placebo<br>Placebo tablet orally administered once daily in the morning before breakfast without food, for the duration of treatment (76 weeks). | Drug: Placebo<br>* 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 (76 weeks).<br>* Other names: Comparator Agent;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 76 Weeks/EOT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 76/EOT | 
| 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 76/EOT | 
| Improvement in steatosis, ballooning, inflammation and fibrosis from liver biopsy | Proportion of subjects with ≥1 point improvement in steatosis, ballooning, inflammation and fibrosis | Week 76/EOT | 
| 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 76/EOT | 
| Histological score changes in steatosis, ballooning, inflammation, and fibrosis | Change from baseline in steatosis, ballooning, inflammation, and fibrosis | Week 76/EOT | 
| 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 and Week 76/EOT | 
| 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 and Week 76/EOT | 
| 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 and Week 76/EOT | 
| Change in body weight (any change from baseline) | Change from baseline in body weight | Week 52 and Week 76/EOT | 
| Change in insulin resistance marker, HOMA-IR | Change from baseline in insulin resistance marker (HOMA-IR) | Week 52 and Week 76/EOT | 
| 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 and Week 76/EOT | 
| Change in glucose homeostasis markers including (HbA1c, FPG) | Change from baseline in glucose homeostasis markers (HbA1c, FPG) | Week 52 and Week 76/EOT | 
| Change from baseline in non-invasive markers of fibrosis | Change from baseline in non-invasive markers of fibrosis (Enhanced Liver Fibrosis [ELF] test, Fibrosis 4 [FIB 4], APRI [AST to Platelet Ratio Index], NFS [NAFLD Fibrosis Score], PRO-C3) | Week 52 and Week 76/EOT | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Saroglitazar Magnesium, Nonalcoholic Steatohepatitis, NASH, Fibrosis