Clinical trial NCT03863574: Saroglitazar Magnesium in the Treatment of Non-Alcoholic Steatohepatitis
Official title: 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 (NASH)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Non Alcoholic Steatohepatitis
Keywords: NASH
Lead sponsor: Zydus Therapeutics Inc.
Sponsor class: INDUSTRY
First posted: 2019-03-05
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: NAS Score (Nonalcoholic Fatty Liver Disease [NAFLD] Activity Score)
timeFrame: Baseline to Week 24
Secondary outcomes:
measure: To Evaluate the Percentage of Responders in the Treatment Groups.
timeFrame: Baseline to Week 24
measure: Percentage of Responders Defined by the Disappearance of Steatohepatitis.
timeFrame: Baseline to Week 24
measure: Changes in the Stage of Steatosis, Lobular Inflammation and Ballooning.
timeFrame: Baseline to Week 24
measure: Changes in the Stage of Fibrosis.
timeFrame: Baseline to Week 24
measure: Changes in the Liver Function Tests; (Alanine Aminotransferase [ALT], Aspartate Aminotransferase [AST], Alkaline Phosphatases [ALP], and Gamma-glutamyl Transferase [GGT]).
timeFrame: Baseline to Week 24
measure: Changes in the Liver Function Tests; Albumin and Total Protein
timeFrame: Baseline to Week 24
measure: Changes in the Liver Function Tests; Direct Bilirubin
timeFrame: Baseline to Week 24
measure: Changes in the Lipid Profile.
timeFrame: Baseline to Week 24
measure: Number of Participants Experiencing Adverse Events After Consuming Saroglitazar Magnesium 2 mg and 4 mg
timeFrame: Baseline to Week 24
measure: Changes in the Glycemic Control and Insulin Resistance; Fasting Plasma Glucose
timeFrame: Baseline to Week 24
measure: Changes in the Glycemic Control and Insulin Resistance; Hemoglobin A1c
timeFrame: Baseline to Week 24
measure: Changes in the Glycemic Control and Insulin Resistance; Insulin
timeFrame: Baseline to Week 24
measure: Changes in the Glycemic Control and Insulin Resistance: C-peptide
timeFrame: Baseline to Week 24
measure: Changes in the Glycemic Control and Insulin Resistance: Homeostasis Model Assessment of Beta Cell Function (HOMA -β)
timeFrame: Baseline to Week 24
measure: Changes in the Glycemic Control and Insulin Resistance: HOMA of Insulin Resistance
timeFrame: Baseline to Week 24
measure: Changes in the Glycemic Control and Insulin Resistance: Total Adiponectin
timeFrame: Baseline to Week 24
Other outcomes:
Locations:
city: Jackson
country: United States
facility: Southern Therapy and Advanced Research (STAR) LLC
state: Mississippi
city: Germantown
country: United States
facility: Gastro One
state: Tennessee
city: Hermitage
country: United States
facility: Digestive Health Research
state: Tennessee
city: San Antonio
country: United States
facility: Texas Liver Institute
state: Texas
city: San Antonio
country: United States
facility: Clinical Trials of Texas, Inc.
state: Texas
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
Study officials:
affiliation: Zydus Therapeutics Inc.
name: Deven V Parmar, MD,FACP,FCP
role: STUDY_DIRECTOR
References:
citation: Siddiqui MS, Parmar D, Sheikh F, Sarin SK, Cisneros L, Gawrieh S, Momin T, Duseja A, Sanyal AJ. Saroglitazar, a Dual PPAR alpha/gamma Agonist, Improves Atherogenic Dyslipidemia in Patients With Non-Cirrhotic Nonalcoholic Fatty Liver Disease: A Pooled Analysis. Clin Gastroenterol Hepatol. 2023 Sep;21(10):2597-2605.e2. doi: 10.1016/j.cgh.2023.01.018. Epub 2023 Jan 31.
citation: Siddiqui MS, Idowu MO, Parmar D, Borg BB, Denham D, Loo NM, Lazas D, Younes Z, Sanyal AJ. A Phase 2 Double Blinded, Randomized Controlled Trial of Saroglitazar in Patients With Nonalcoholic Steatohepatitis. Clin Gastroenterol Hepatol. 2021 Dec;19(12):2670-2672. doi: 10.1016/j.cgh.2020.10.051. Epub 2020 Nov 2.