Saroglitazar Magnesium in the Treatment of Non-Alcoholic Steatohepatitis

Phase 2

Completed

• Conditions: Non Alcoholic Steatohepatitis
• Interventions: Drug: Saroglitazar Magnesium 4mg; Drug: Placebos; Drug: Saroglitazar Magnesium 2mg

• Registration Number: NCT03863574
• Lead Sponsor: Zydus Therapeutics Inc.

Brief Summary

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

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 Non-alcoholic fatty liver disease (NAFLD) Activity Score (NAS). 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.

Study Timeline

• Study First Submitted: 2019-02-24
• Study First Submitted QC: 2019-03-04
• Study First Posted: 2019-03-05
• Study Start: 2019-06-12
• Primary Completion: 2020-03-20
• Study Completion: 2020-03-20
• Results First Submitted: 2024-07-16
• Status Verified: 2024-09
• Results First Submitted QC: 2024-09-17
• Last Update Submitted: 2024-09-17
• Results First Posted: 2024-10-11
• Last Update Posted: 2024-10-11

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 16

Inclusion Criteria

1. Patients able to provide written informed consent for participation in this trial.

2. Males or females, 18 to 75 years of age, both inclusive.

3. 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.

4. 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.

5. BMI ≥25 kg/m^2.

6. 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)

7. Patients with type 2 diabetes mellitus may be included if they fulfil the following criteria;

   1. 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.
   2. HbA1c ≤ 9.5%

8. Patients agree to comply with the study procedure.

Exclusion Criteria

1. Pregnant and lactating female.

2. Positive pregnancy test.

3. Patients with history of myopathies or evidence of active muscle diseases.

4. 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.

5. Known allergy, sensitivity or intolerance to the study drug or formulation ingredients.

6. Participation in an interventional clinical study and/or receipt of any investigational medication within 3 months prior to screening.

7. History of malignancy in the past 5 years and/or active neoplasm with the exception of superficial, non-melanoma, skin cancer.

8. Any of the following laboratory values at screening:

   1. Direct bilirubin >1.5 mg/dL,
   2. Serum albumin <2.5 g/dL.
   3. Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2.
   4. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >200 IU/L.
   5. Patient with international normalized ratio (INR) >1.5.
   6. Creatinine kinase ≥ 1.5 upper limit of normal (ULN).
   7. Lipase ≥ULN.
   8. Amylase ≥ ULN.

9. Unstable cardiovascular disease, including:

   1. 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
   2. history of (within 3 months preceding Screening) or current unstable cardiac dysrhythmias
   3. uncontrolled hypertension (systolic blood pressure [BP] > 155 mmHg and/or diastolic BP > 95 mmHg)
   4. Stroke or transient ischemic attack within the 6 months preceding screening.

10. Previous history of bladder disease and/or hematuria.

11. Previous liver biopsy that demonstrated presence of cirrhosis or radiologic imaging consistent with cirrhosis or portal hypertension.

12. Type 1 diabetes mellitus.

13. Use of drugs that are known Cytochrome P4502C8 (CYP2C8) inhibitors/substrate.

14. 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).

15. History of thyroid disease (hypothyroid patients who are euthyroid on thyroid hormone replacement can be included).

16. History of, or current, cardiac dysrhythmias.

17. History of bariatric surgery, or undergoing evaluation for bariatric surgery.

18. Patients with a >10% weight loss in the 3 months prior to screening.

19. 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).

20. 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).

21. 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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Saroglitazar Magnesium 4 mg	Saroglitazar Magnesium 4mg	Saroglitazar Magnesium 4 mg tablet orally once daily in the morning before breakfast for 24 weeks.
Placebo	Placebos	Placebo tablet orally once daily in the morning before breakfast for 24 weeks.
Saroglitazar Magnesium 2 mg	Saroglitazar Magnesium 2mg	Saroglitazar Magnesium 2 mg tablet orally once daily in the morning before breakfast for 24 weeks.

Primary Outcome Measures

Name	Time	Method
NAS Score (Nonalcoholic Fatty Liver Disease [NAFLD] Activity Score)	Baseline to Week 24	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.; NAFLD Activity Score Steatosis \<5% - 0 5% -33% - 1 \>33% -66% - 2 \>66% - 3 Lobular Inflammation No foci - 0 \<2 foci per 200 X field -1 2-4 foci per 200 X field - 2 \>4 foci per 200 X field - 3 Ballooning None - 0 Few balloon cells -1 Many cells/prominent ballooning - 2 Final NAFLD Activity Score = Steatosis Score + Lobular Inflammation Score + Ballooning Score Minimum score for NAS is 0 Maximum score for NAS is 8 Higher score represents the worse disease activity

Secondary Outcome Measures

Name	Time	Method
To Evaluate the Percentage of Responders in the Treatment Groups.	Baseline to Week 24	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.
Percentage of Responders Defined by the Disappearance of Steatohepatitis.	Baseline to Week 24	Percentage of responders defined by the disappearance of steatohepatitis
Changes in the Stage of Steatosis, Lobular Inflammation and Ballooning.	Baseline to Week 24	Changes in the stage of steatosis, lobular inflammation and ballooning by evaluating the NAS Score (Nonalcoholic fatty liver disease Activity Score); Steatosis \<5% - 0 5% -33% - 1 \>33% -66% - 2 \>66% - 3 Lobular Inflammation No foci - 0 \<2 foci per 200 X field -1 2-4 foci per 200 X field - 2 \>4 foci per 200 X field - 3 Ballooning None - 0 Few balloon cells -1 Many cells/prominent ballooning - 2 Higher score represents the worse disease activity
Changes in the Stage of Fibrosis.	Baseline to Week 24	Changes in the stage of fibrosis by evaluating the Fibrosis stages; Fibrosis Score; Definition None - 0 Perisinusoidal or periportal - 1 Mild, zone 3, perisinusoidal - 1A Moderate, zone3, perisinusoidal -1B Portal/periportal -1C Perisinusoidal and portal/periportal - 2 Bridging fibrosis - 3 Cirrhosis - 4 Higher score represents the worse disease activity
Changes in the Liver Function Tests; (Alanine Aminotransferase [ALT], Aspartate Aminotransferase [AST], Alkaline Phosphatases [ALP], and Gamma-glutamyl Transferase [GGT]).	Baseline to Week 24	Liver function tests include ALT, AST, ALP, GGT
Changes in the Liver Function Tests; Albumin and Total Protein	Baseline to Week 24	Changes in albumin and total protein
Changes in the Liver Function Tests; Direct Bilirubin	Baseline to Week 24	Change in direct bilirubin
Changes in the Lipid Profile.	Baseline to Week 24	Evaluation of Lipid profile parameters
Number of Participants Experiencing Adverse Events After Consuming Saroglitazar Magnesium 2 mg and 4 mg	Baseline to Week 24	Number of Participants with Adverse Events.
Changes in the Glycemic Control and Insulin Resistance; Fasting Plasma Glucose	Baseline to Week 24	Evaluation of Fasting Plasma Glucose
Changes in the Glycemic Control and Insulin Resistance; Hemoglobin A1c	Baseline to Week 24	Evaluation of Hemoglobin A1c
Changes in the Glycemic Control and Insulin Resistance; Insulin	Baseline to Week 24	Evaluation of Insulin
Changes in the Glycemic Control and Insulin Resistance: C-peptide	Baseline to Week 24	Evaluation of C-peptide
Changes in the Glycemic Control and Insulin Resistance: Homeostasis Model Assessment of Beta Cell Function (HOMA -β)	Baseline to Week 24	Evaluation of HOMA of Beta Cell Function Homeostasis model assessment of beta cell function measures as following; HOMA -β = fasting insulin (μU/mL) ×360/{fasting glucose (mg/dL) - 63}.; HOMA-B provides a quantitative estimate of beta-cell function. A lower HOMA-B value indicates reduced beta-cell function, which can be a sign of progressing towards or already having type 2 diabetes. Conversely, a higher HOMA-B value suggests better beta-cell functionality.
Changes in the Glycemic Control and Insulin Resistance: HOMA of Insulin Resistance	Baseline to Week 24	Evaluation of HOMA of Insulin Resistance Insulin Resistance Index measures insulin resistance, 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.
Changes in the Glycemic Control and Insulin Resistance: Total Adiponectin	Baseline to Week 24	Evaluation of Total Adiponectin

Trial Locations

Locations (6)

Texas Liver Institute; 🇺🇸 San Antonio, Texas, United States

Southern Therapy and Advanced Research (STAR) LLC; 🇺🇸 Jackson, Mississippi, United States

Gastro One; 🇺🇸 Germantown, Tennessee, United States

Digestive Health Research; 🇺🇸 Hermitage, Tennessee, United States

Clinical Trials of Texas, Inc.; 🇺🇸 San Antonio, Texas, United States

Virginia Commonwealth University; 🇺🇸 Richmond, Virginia, United States