Saroglitazar Magnesium in the Treatment of Non-Alcoholic Steatohepatitis

Study Overview
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Brief Summary
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This is a randomized, double-blind, placebo-controlled study to evaluate safety and efficacy of Saroglitazar Magnesium 2 mg and 4 mg in patients with NASH. This study will be initiated after obtaining the approvals of Institutional Ethics Committee/Institutional Review Board (IEC/IRB) and the local regulatory authority.

Detailed Description
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Patients clinically suspected of NASH will be invited for a screening programme for inclusion in the study. Patients will be screened according to the inclusion and exclusion criteria. Clinical evaluation will be conducted for baseline characteristics and anthropometry measurements such as body weight and height. After clinical evaluations, all baseline safety and efficacy parameters will be recorded as per Visit Schedule. All laboratory collections will be performed following overnight fasting (at least 8 hrs). Following confirmation of all clinical and laboratory inclusion and exclusion criteria, patients will continue into the screening period. During the screening period liver biopsy will be performed. However, if a biopsy was performed within 6 months the slides and biopsy material, or block, must be made available for baseline documentation. Such Patients, whose historical biopsy report is available, should not use medication suspected of having an effect on NASH from the 3 months prior to the screening. Liver biopsy will be performed to confirm the diagnosis of NASH and record a baseline NAFLD Activity Score. The histological evidence of NASH is defined as NAS ≥ 4 with a minimum score of 1 for all of its three components [steatosis, hepatocyte ballooning and lobular inflammation]. Following confirmation of inclusion/exclusion criteria and upon histological confirmation of NASH by liver biopsy, patients will be enrolled into the study. Eligible patients will be randomly assigned to receive Saroglitazar Magnesium 2 mg or 4 mg or placebo in a 2:2:1 ratio for 24 weeks. Upon completion of 24 weeks of treatment, liver biopsy will be performed and the NAFLD Activity Score recorded.

Official Title
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A Phase 2, Prospective, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety and Efficacy of Saroglitazar Magnesium 2 mg and 4 mg in Patients With Non-alcoholic Steatohepatitis

Conditions
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Non Alcoholic Steatohepatitis

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients able to provide written informed consent for participation in this trial. Males or females, 18 to 75 years of age, both inclusive. Female must be either of non-child bearing potential (surgically sterilized at least 6 months prior to screening or postmenopausal) or using one or more methods of contraception. Histologic confirmation of NASH without cirrhosis (fibrosis stage 0, 1, 2, or 3) from liver biopsy performed either during the screening period or no more than 6 months prior to the first visit, with a NAS of ≥4 and a score of at least 1 in each (steatosis scored 0-3, ballooning scored 0-2, and lobular inflammation scored 0-3). If biopsy was performed within 6 months of screening, the slides, biopsy material or block should be available for baseline documentation. Such patients, whose historical biopsy report is available, should not use medications suspected of having an effect on NASH for at least 3 months prior to the screening. BMI ≥25 kg/m2. For hypertensive patients, blood pressure must be controlled by a stable dose of antihypertensive medications for at least 3 months prior to screening (and the stable dose can be maintained throughout the study) Patients with type 2 diabetes mellitus may be included if they fulfil the following criteria; Stable therapeutic regimen as defined by no changes in oral agents or dose for at least 3 months before screening and the stable dose can be maintained throughout the study. HbA1c ≤ 9.5% Patients agree to comply with the study procedure. Exclusion Criteria: Pregnant and lactating female. Positive pregnancy test. Patients with history of myopathies or evidence of active muscle diseases. Patients with history of alcohol consumption of >30 gm/day for men, >20 gm/day for women for consecutive previous 2 years and/or drug abuse. Known allergy, sensitivity or intolerance to the study drug or formulation ingredients. Participation in an interventional clinical study and/or receipt of any investigational medication within 3 months prior to screening. History of malignancy in the past 5 years and/or active neoplasm with the exception of superficial, non-melanoma, skin cancer. Any of the following laboratory values at screening: Direct bilirubin >1.5 mg/dL, Serum albumin <2.5 g/dL. Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >200 IU/L. Patient with international normalized ratio (INR) >1.5. Creatinine kinase ≥ 1.5 ULN. Lipase ≥ULN. Amylase ≥ ULN. Unstable cardiovascular disease, including: unstable angina, (i.e., new or worsening symptoms of coronary heart disease within the 3 months preceding screening), acute coronary syndrome within the 6 months preceding Screening, acute myocardial infarction within the 3 months preceding screening or heart failure of New York Heart Association class (III - IV) or worsening congestive heart failure, or coronary artery intervention, within the 6 months preceding screening history of (within 3 months preceding Screening) or current unstable cardiac dysrhythmias uncontrolled hypertension (systolic blood pressure [BP] > 155 mmHg and/or diastolic BP > 95 mmHg) Stroke or transient ischemic attack within the 6 months preceding screening. Previous history of bladder disease and/or hematuria. Previous liver biopsy that demonstrated presence of cirrhosis or radiologic imaging consistent with cirrhosis or portal hypertension. Type 1 diabetes mellitus. Use of drugs that are known CYP2C8 inhibitors/substrate. Use of drugs associated with a clinical or histological picture consistent with fatty liver disease or NASH for more than 12 consecutive weeks in the 1 year prior to start of the study; (these include amiodarone, tamoxifen, methotrexate, glucocorticoids, anabolic steroids, tetracyclines, estrogens, valproate/valproic acid, chloroquine, anti-HIV drugs). History of thyroid disease (hypothyroid patients who are euthyroid on thyroid hormone replacement can be included). History of, or current, cardiac dysrhythmias. History of bariatric surgery, or undergoing evaluation for bariatric surgery. Patients with a >10% weight loss in the 3 months prior to screening. History or other evidence of severe illness or any other conditions that would make the patient, in the opinion of the Investigator, unsuitable for the study (such as poorly controlled psychiatric disease, coronary artery disease, HIV or active gastrointestinal conditions that might interfere with drug absorption). Patients on any treatment with other drugs used for treatment of NASH [pentoxyphyllin, ursodeoxycholic acid, antioxidants such as vitamin E (>800 IU/day), glutathione, orlistat, betaine, incretin mimetics or non-prescribed complementary alternative medications (including dietary supplements, megadose vitamins, herbal preparations and special teas)] or any medicine in clinical trials for NASH. (However, patients who are taking stable dose of vitamin E for at least 3 months prior to screening will be enrolled in the study). History of other causes of chronic liver disease [autoimmune, primary biliary cirrhosis, hepatitis B virus (HBV) and hepatitis C virus (HCV), Wilson disease, alpha-1-antitrypsin deficiency, hemochromatosis etc.

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
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Saroglitazar Magnesium 2 mg<br>Saroglitazar Magnesium 2 mg tablet orally once daily in the morning before breakfast for 24 weeks. | Drug: Saroglitazar Magnesium 2mg<br>* Patients randomly assigned to this group will receive Saroglitazar Magnesium 2 mg tablet orally once daily for 24 weeks.<br>|
| Experimental: Saroglitazar Magnesium 4 mg<br>Saroglitazar Magnesium 4 mg tablet orally once daily in the morning before breakfast for 24 weeks. | Drug: Saroglitazar Magnesium 4mg<br>* Patients randomly assigned to this group will receive Saroglitazar Magnesium 4 mg tablet orally once daily for 24 weeks.<br>|
| Placebo Comparator: Placebo<br>Placebo tablet orally once daily in the morning before breakfast for 24 weeks. | Drug: Placebos<br>* Patients randomly assigned to this group will receive Placebo tablet orally once daily for 24 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| NAS Score (NAFLD Activity Score) | The primary endpoint is to assess the changes in NAFLD Activity Score (NAS) at week 24 from baseline and with no worsening of fibrosis in NASH patients. | Baseline to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the percentage of responders in the treatment groups. | Responder is defined as a decrease from baseline of at least 2 points spread across at least 2 of the NAS components [steatosis, hepatocyte ballooning, and lobular inflammation] with no worsening of fibrosis. | Baseline to Week 24 | 
| Percentage of responders defined by the disappearance of steatohepatitis. | Percentage of responders defined by the disappearance of steatohepatitis. | Baseline to Week 24 | 
| Changes in the stage of steatosis, lobular inflammation and ballooning. | Changes in the stage of steatosis, lobular inflammation and ballooning by evaluating the NAS Score (NAFLD Activity Score) | Baseline to Week 24 | 
| Changes in the stage of fibrosis. | Changes in the stage of fibrosis by evaluating the Fibrosis stages | Baseline to Week 24 | 
| Changes in the liver function tests. | Liver function tests include ALT, AST, ALP, direct bilirubin, GGT, total proteins and albumin. | Baseline to Week 24 | 
| Changes in the lipid profile. | Evaluation of Lipid profile parameters | Baseline to Week 24 | 
| Changes in the glycemic control and insulin resistance. | Evaluation of glycemic control and insulin resistance. | Baseline to Week 24 | 
| To assess incidence of Adverse Events of Saroglitazar Magnesium 2 mg and 4 mg in patients with non-alcoholic steatohepatitis. | Safety will be assessed during the study period through the reporting of AEs. | Baseline to Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NASH