Non Alcoholic Steatohepatitis
Conditions
Keywords
NASH
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.
Interventions
DRUGSaroglitazar Magnesium 2mg
Patients randomly assigned to this group will receive Saroglitazar Magnesium 2 mg tablet orally once daily for 24 weeks.
Patients randomly assigned to this group will receive Saroglitazar Magnesium 4 mg tablet orally once daily for 24 weeks.
DRUGPlacebos
Patients randomly assigned to this group will receive Placebo tablet orally once daily for 24 weeks.
Sponsors
Zydus Therapeutics Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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. |
| 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 |
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Saroglitazar Magnesium 2 mg Saroglitazar Magnesium 2 mg tablet orally once daily in the morning before breakfast for 24 weeks.
Saroglitazar Magnesium 2mg: Patients randomly assigned to this group will receive Saroglitazar Magnesium 2 mg tablet orally once daily for 24 weeks. | 6 |
| Saroglitazar Magnesium 4 mg Saroglitazar Magnesium 4 mg tablet orally once daily in the morning before breakfast for 24 weeks.
Saroglitazar Magnesium 4mg: Patients randomly assigned to this group will receive Saroglitazar Magnesium 4 mg tablet orally once daily for 24 weeks. | 7 |
| Placebo Placebo tablet orally once daily in the morning before breakfast for 24 weeks.
Placebos: Patients randomly assigned to this group will receive Placebo tablet orally once daily for 24 weeks. | 3 |
| Total | 16 |
Baseline characteristics
| Characteristic | Saroglitazar Magnesium 2 mg | Saroglitazar Magnesium 4 mg | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 48.67 Years STANDARD_DEVIATION 9.91 | 50.57 Years STANDARD_DEVIATION 16.48 | 63.33 Years STANDARD_DEVIATION 8.08 | 52.25 Years STANDARD_DEVIATION 13.46 |
| Body Mass Index | 37.32 kg/m^2 STANDARD_DEVIATION 5.85 | 37.89 kg/m^2 STANDARD_DEVIATION 8.27 | 37.67 kg/m^2 STANDARD_DEVIATION 12.76 | 37.63 kg/m^2 STANDARD_DEVIATION 7.78 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 3 Participants | 1 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 3 Participants | 2 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 7 Participants | 2 Participants | 14 Participants |
| Region of Enrollment United States | 6 Participants | 7 Participants | 3 Participants | 16 Participants |
| Sex: Female, Male Female | 5 Participants | 6 Participants | 3 Participants | 14 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 7 | 0 / 3 |
| other Total, other adverse events | 3 / 6 | 5 / 7 | 2 / 3 |
| serious Total, serious adverse events | 0 / 6 | 2 / 7 | 0 / 3 |
Outcome results
Primary
NAS Score (Nonalcoholic Fatty Liver Disease [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. 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
Time frame: Baseline to Week 24
Population: modified intention-to-treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saroglitazar Magnesium 2 mg | NAS Score (Nonalcoholic Fatty Liver Disease [NAFLD] Activity Score) | -1.50 units on a scale | Standard Deviation 0.84 |
| Saroglitazar Magnesium 4 mg | NAS Score (Nonalcoholic Fatty Liver Disease [NAFLD] Activity Score) | -1.86 units on a scale | Standard Deviation 1.57 |
| Placebo | NAS Score (Nonalcoholic Fatty Liver Disease [NAFLD] Activity Score) | -1.33 units on a scale | Standard Deviation 0.58 |
p-value: 0.7689t-test, 2 sided
p-value: 0.6007t-test, 2 sided
Secondary
Changes in the Glycemic Control and Insulin Resistance: C-peptide
Evaluation of C-peptide
Time frame: Baseline to Week 24
Population: modified intent-to-treat population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saroglitazar Magnesium 2 mg | Changes in the Glycemic Control and Insulin Resistance: C-peptide | -1.09 ng/mL | Standard Deviation 2.26 |
| Saroglitazar Magnesium 4 mg | Changes in the Glycemic Control and Insulin Resistance: C-peptide | 0.08 ng/mL | Standard Deviation 1.41 |
| Placebo | Changes in the Glycemic Control and Insulin Resistance: C-peptide | 0.27 ng/mL | Standard Deviation 0.95 |
p-value: 0.3605t-test, 2 sided
p-value: 0.8394t-test, 2 sided
Secondary
Changes in the Glycemic Control and Insulin Resistance; Fasting Plasma Glucose
Evaluation of Fasting Plasma Glucose
Time frame: Baseline to Week 24
Population: modified intent-to-treat population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saroglitazar Magnesium 2 mg | Changes in the Glycemic Control and Insulin Resistance; Fasting Plasma Glucose | 2.67 mg/dL | Standard Deviation 19.18 |
| Saroglitazar Magnesium 4 mg | Changes in the Glycemic Control and Insulin Resistance; Fasting Plasma Glucose | -0.86 mg/dL | Standard Deviation 41.1 |
| Placebo | Changes in the Glycemic Control and Insulin Resistance; Fasting Plasma Glucose | 7.67 mg/dL | Standard Deviation 12.5 |
p-value: 0.6988t-test, 2 sided
p-value: 0.7413t-test, 2 sided
Secondary
Changes in the Glycemic Control and Insulin Resistance; Hemoglobin A1c
Evaluation of Hemoglobin A1c
Time frame: Baseline to Week 24
Population: modified intent-to-treat population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saroglitazar Magnesium 2 mg | Changes in the Glycemic Control and Insulin Resistance; Hemoglobin A1c | -0.52 percentage of HbA1c | Standard Deviation 0.65 |
| Saroglitazar Magnesium 4 mg | Changes in the Glycemic Control and Insulin Resistance; Hemoglobin A1c | -0.09 percentage of HbA1c | Standard Deviation 0.28 |
| Placebo | Changes in the Glycemic Control and Insulin Resistance; Hemoglobin A1c | 0.03 percentage of HbA1c | Standard Deviation 0.35 |
p-value: 0.22t-test, 2 sided
p-value: 0.5798t-test, 2 sided
Secondary
Changes in the Glycemic Control and Insulin Resistance: HOMA of Insulin Resistance
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.
Time frame: Baseline to Week 24
Population: modified intent-to-treat population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saroglitazar Magnesium 2 mg | Changes in the Glycemic Control and Insulin Resistance: HOMA of Insulin Resistance | 0.45 percentage of HOMA of Insulin Resistance | Standard Deviation 8.3 |
| Saroglitazar Magnesium 4 mg | Changes in the Glycemic Control and Insulin Resistance: HOMA of Insulin Resistance | 2.73 percentage of HOMA of Insulin Resistance | Standard Deviation 5.77 |
| Placebo | Changes in the Glycemic Control and Insulin Resistance: HOMA of Insulin Resistance | 2.34 percentage of HOMA of Insulin Resistance | Standard Deviation 4.18 |
p-value: 0.7267t-test, 2 sided
p-value: 0.9211t-test, 2 sided
Secondary
Changes in the Glycemic Control and Insulin Resistance: Homeostasis Model Assessment of Beta Cell Function (HOMA -β)
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.
Time frame: Baseline to Week 24
Population: modified intent-to-treat population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saroglitazar Magnesium 2 mg | Changes in the Glycemic Control and Insulin Resistance: Homeostasis Model Assessment of Beta Cell Function (HOMA -β) | -34.35 percentage of HOMA of Beta Cell Function | Standard Deviation 84.41 |
| Saroglitazar Magnesium 4 mg | Changes in the Glycemic Control and Insulin Resistance: Homeostasis Model Assessment of Beta Cell Function (HOMA -β) | 14.49 percentage of HOMA of Beta Cell Function | Standard Deviation 358.04 |
| Placebo | Changes in the Glycemic Control and Insulin Resistance: Homeostasis Model Assessment of Beta Cell Function (HOMA -β) | 30.10 percentage of HOMA of Beta Cell Function | Standard Deviation 46.15 |
p-value: 0.2665t-test, 2 sided
p-value: 0.9133t-test, 2 sided
Secondary
Changes in the Glycemic Control and Insulin Resistance; Insulin
Evaluation of Insulin
Time frame: Baseline to Week 24
Population: modified intent-to-treat population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saroglitazar Magnesium 2 mg | Changes in the Glycemic Control and Insulin Resistance; Insulin | -1.05 μIU/mL | Standard Deviation 20.05 |
| Saroglitazar Magnesium 4 mg | Changes in the Glycemic Control and Insulin Resistance; Insulin | 6.74 μIU/mL | Standard Deviation 15.34 |
| Placebo | Changes in the Glycemic Control and Insulin Resistance; Insulin | 8.13 μIU/mL | Standard Deviation 12.32 |
p-value: 0.4981t-test, 2 sided
p-value: 0.8939t-test, 2 sided
Secondary
Changes in the Glycemic Control and Insulin Resistance: Total Adiponectin
Evaluation of Total Adiponectin
Time frame: Baseline to Week 24
Population: modified intent-to-treat population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saroglitazar Magnesium 2 mg | Changes in the Glycemic Control and Insulin Resistance: Total Adiponectin | 1.84 μg/mL | Standard Deviation 2.17 |
| Saroglitazar Magnesium 4 mg | Changes in the Glycemic Control and Insulin Resistance: Total Adiponectin | 0.68 μg/mL | Standard Deviation 3.28 |
| Placebo | Changes in the Glycemic Control and Insulin Resistance: Total Adiponectin | 1.50 μg/mL | Standard Deviation 4.02 |
p-value: 0.8683t-test, 2 sided
p-value: 0.7436t-test, 2 sided
Secondary
Changes in the Lipid Profile.
Evaluation of Lipid profile parameters
Time frame: Baseline to Week 24
Population: Modified intent-to-treat population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Saroglitazar Magnesium 2 mg | Changes in the Lipid Profile. | Change in non-HDL Cholesterol | 4.83 mg/dL | Standard Deviation 33.68 |
| Saroglitazar Magnesium 2 mg | Changes in the Lipid Profile. | Change in High-density Lipoprotein | 6.33 mg/dL | Standard Deviation 14.85 |
| Saroglitazar Magnesium 2 mg | Changes in the Lipid Profile. | Change in Total Cholesterol | 11.17 mg/dL | Standard Deviation 40.45 |
| Saroglitazar Magnesium 2 mg | Changes in the Lipid Profile. | Change in Very low-density lipoprotein | -8.17 mg/dL | Standard Deviation 7.41 |
| Saroglitazar Magnesium 2 mg | Changes in the Lipid Profile. | Change in Low-density lipoprotein | 13.00 mg/dL | Standard Deviation 34.89 |
| Saroglitazar Magnesium 2 mg | Changes in the Lipid Profile. | Change in Triglyceride | -40.33 mg/dL | Standard Deviation 38.37 |
| Saroglitazar Magnesium 2 mg | Changes in the Lipid Profile. | Change in Apo lipoprotein A1 | 10.50 mg/dL | Standard Deviation 36.74 |
| Saroglitazar Magnesium 2 mg | Changes in the Lipid Profile. | Change in Small dense LDL | 1.27 mg/dL | Standard Deviation 15.99 |
| Saroglitazar Magnesium 2 mg | Changes in the Lipid Profile. | Change in Apo lipoprotein B | 1.00 mg/dL | Standard Deviation 26.53 |
| Saroglitazar Magnesium 4 mg | Changes in the Lipid Profile. | Change in Low-density lipoprotein | -12.57 mg/dL | Standard Deviation 28.11 |
| Saroglitazar Magnesium 4 mg | Changes in the Lipid Profile. | Change in Triglyceride | -16.71 mg/dL | Standard Deviation 44.31 |
| Saroglitazar Magnesium 4 mg | Changes in the Lipid Profile. | Change in Total Cholesterol | -16.00 mg/dL | Standard Deviation 31.12 |
| Saroglitazar Magnesium 4 mg | Changes in the Lipid Profile. | Change in Small dense LDL | -9.29 mg/dL | Standard Deviation 11.85 |
| Saroglitazar Magnesium 4 mg | Changes in the Lipid Profile. | Change in High-density Lipoprotein | -0.14 mg/dL | Standard Deviation 8.47 |
| Saroglitazar Magnesium 4 mg | Changes in the Lipid Profile. | Change in Very low-density lipoprotein | -3.29 mg/dL | Standard Deviation 8.88 |
| Saroglitazar Magnesium 4 mg | Changes in the Lipid Profile. | Change in non-HDL Cholesterol | -15.86 mg/dL | Standard Deviation 29.23 |
| Saroglitazar Magnesium 4 mg | Changes in the Lipid Profile. | Change in Apo lipoprotein A1 | -14.29 mg/dL | Standard Deviation 26.98 |
| Saroglitazar Magnesium 4 mg | Changes in the Lipid Profile. | Change in Apo lipoprotein B | -14.71 mg/dL | Standard Deviation 21.04 |
| Placebo | Changes in the Lipid Profile. | Change in Small dense LDL | 5.87 mg/dL | Standard Deviation 6.66 |
| Placebo | Changes in the Lipid Profile. | Change in Triglyceride | -6.00 mg/dL | Standard Deviation 34.04 |
| Placebo | Changes in the Lipid Profile. | Change in non-HDL Cholesterol | -7.33 mg/dL | Standard Deviation 9.29 |
| Placebo | Changes in the Lipid Profile. | Change in Total Cholesterol | -0.33 mg/dL | Standard Deviation 9.02 |
| Placebo | Changes in the Lipid Profile. | Change in Apo lipoprotein B | -1.33 mg/dL | Standard Deviation 4.62 |
| Placebo | Changes in the Lipid Profile. | Change in Low-density lipoprotein | -6.00 mg/dL | Standard Deviation 5.29 |
| Placebo | Changes in the Lipid Profile. | Change in High-density Lipoprotein | 7.00 mg/dL | Standard Deviation 4.36 |
| Placebo | Changes in the Lipid Profile. | Change in Apo lipoprotein A1 | 7.33 mg/dL | Standard Deviation 2.08 |
| Placebo | Changes in the Lipid Profile. | Change in Very low-density lipoprotein | -1.33 mg/dL | Standard Deviation 6.51 |
Comparison: Outcome Variable: Triglyceridep-value: 0.2329t-test, 2 sided
Comparison: Outcome Variable: Triglyceridep-value: 0.7211t-test, 2 sided
Comparison: Outcome Variables: Total Cholesterolp-value: 0.652t-test, 2 sided
Comparison: Outcome Variable: Total Cholesterolp-value: 0.4302t-test, 2 sided
Comparison: Outcome Variable: High-density Lipoproteinp-value: 0.9432t-test, 2 sided
Comparison: Outcome Variable: High-density Lipoproteinp-value: 0.2133t-test, 2 sided
Comparison: Outcome Variable: Low-density lipoproteinp-value: 0.2446t-test, 2 sided
Comparison: Outcome Variable: Low-density lipoproteinp-value: 0.7075t-test, 2 sided
Comparison: Outcome Variable: Very low-density lipoproteinp-value: 0.2195t-test, 2 sided
Comparison: Outcome Variable: Very low-density lipoproteinp-value: 0.7435t-test, 2 sided
Comparison: Outcome Variable: non-HDL Cholesterolp-value: 0.5702t-test, 2 sided
Comparison: Outcome Variable: non-HDL Cholesterolp-value: 0.6441t-test, 2 sided
Comparison: Outcome Variable: Apo lipoprotein A1p-value: 0.8415t-test, 2 sided
Comparison: Outcome Variable: Apo lipoprotein A1p-value: 0.0786t-test, 2 sided
Comparison: Outcome Variable: Apo lipoprotein Bp-value: 0.8878t-test, 2 sided
Comparison: Outcome variable: Apo lipoprotein Bp-value: 0.3219t-test, 2 sided
Comparison: Outcome Variable: Small dense LDLp-value: 0.6557t-test, 2 sided
Comparison: Outcome Variable: Small dense LDLp-value: 0.0763t-test, 2 sided
Secondary
Changes in the Liver Function Tests; (Alanine Aminotransferase [ALT], Aspartate Aminotransferase [AST], Alkaline Phosphatases [ALP], and Gamma-glutamyl Transferase [GGT]).
Liver function tests include ALT, AST, ALP, GGT
Time frame: Baseline to Week 24
Population: Modified intent-to-treat population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Saroglitazar Magnesium 2 mg | Changes in the Liver Function Tests; (Alanine Aminotransferase [ALT], Aspartate Aminotransferase [AST], Alkaline Phosphatases [ALP], and Gamma-glutamyl Transferase [GGT]). | Change in ALT | -22.83 U/L | Standard Deviation 14.29 |
| Saroglitazar Magnesium 2 mg | Changes in the Liver Function Tests; (Alanine Aminotransferase [ALT], Aspartate Aminotransferase [AST], Alkaline Phosphatases [ALP], and Gamma-glutamyl Transferase [GGT]). | Change in AST | -10.33 U/L | Standard Deviation 5.32 |
| Saroglitazar Magnesium 2 mg | Changes in the Liver Function Tests; (Alanine Aminotransferase [ALT], Aspartate Aminotransferase [AST], Alkaline Phosphatases [ALP], and Gamma-glutamyl Transferase [GGT]). | Change in ALP | -24.00 U/L | Standard Deviation 9.92 |
| Saroglitazar Magnesium 2 mg | Changes in the Liver Function Tests; (Alanine Aminotransferase [ALT], Aspartate Aminotransferase [AST], Alkaline Phosphatases [ALP], and Gamma-glutamyl Transferase [GGT]). | Change in GGT | -23.83 U/L | Standard Deviation 18.55 |
| Saroglitazar Magnesium 4 mg | Changes in the Liver Function Tests; (Alanine Aminotransferase [ALT], Aspartate Aminotransferase [AST], Alkaline Phosphatases [ALP], and Gamma-glutamyl Transferase [GGT]). | Change in GGT | -28.43 U/L | Standard Deviation 33.3 |
| Saroglitazar Magnesium 4 mg | Changes in the Liver Function Tests; (Alanine Aminotransferase [ALT], Aspartate Aminotransferase [AST], Alkaline Phosphatases [ALP], and Gamma-glutamyl Transferase [GGT]). | Change in ALT | -29.57 U/L | Standard Deviation 26.76 |
| Saroglitazar Magnesium 4 mg | Changes in the Liver Function Tests; (Alanine Aminotransferase [ALT], Aspartate Aminotransferase [AST], Alkaline Phosphatases [ALP], and Gamma-glutamyl Transferase [GGT]). | Change in ALP | -23.86 U/L | Standard Deviation 15.18 |
| Saroglitazar Magnesium 4 mg | Changes in the Liver Function Tests; (Alanine Aminotransferase [ALT], Aspartate Aminotransferase [AST], Alkaline Phosphatases [ALP], and Gamma-glutamyl Transferase [GGT]). | Change in AST | -16.29 U/L | Standard Deviation 11.63 |
| Placebo | Changes in the Liver Function Tests; (Alanine Aminotransferase [ALT], Aspartate Aminotransferase [AST], Alkaline Phosphatases [ALP], and Gamma-glutamyl Transferase [GGT]). | Change in GGT | -1.67 U/L | Standard Deviation 19.5 |
| Placebo | Changes in the Liver Function Tests; (Alanine Aminotransferase [ALT], Aspartate Aminotransferase [AST], Alkaline Phosphatases [ALP], and Gamma-glutamyl Transferase [GGT]). | Change in AST | -19.33 U/L | Standard Deviation 47.44 |
| Placebo | Changes in the Liver Function Tests; (Alanine Aminotransferase [ALT], Aspartate Aminotransferase [AST], Alkaline Phosphatases [ALP], and Gamma-glutamyl Transferase [GGT]). | Change in ALP | 3.67 U/L | Standard Deviation 5.13 |
| Placebo | Changes in the Liver Function Tests; (Alanine Aminotransferase [ALT], Aspartate Aminotransferase [AST], Alkaline Phosphatases [ALP], and Gamma-glutamyl Transferase [GGT]). | Change in ALT | -14.67 U/L | Standard Deviation 48.95 |
Comparison: Outcome variable: Alanine Aminotransferasep-value: 0.8019t-test, 2 sided
Comparison: Outcome Variable: Alanine Aminotransferasep-value: 0.5396t-test, 2 sided
Comparison: Outcome Variable: Aspartate Aminotransferasep-value: 0.774t-test, 2 sided
Comparison: Outcome Variable: Aspartate Aminotransferasep-value: 0.9221t-test, 2 sided
Comparison: Outcome Variable: Alkaline Phosphatasep-value: 0.003t-test, 2 sided
Comparison: Outcome Variable: Alkaline Phosphatasep-value: 0.0177t-test, 2 sided
Comparison: Outcome Variable: Gamma Glutamyl Transferasep-value: 0.1399t-test, 2 sided
Comparison: Outcome Variable: Gamma Glutamyl Transferasep-value: 0.2384t-test, 2 sided
Secondary
Changes in the Liver Function Tests; Albumin and Total Protein
Changes in albumin and total protein
Time frame: Baseline to Week 24
Population: Modified intend-to-treat population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Saroglitazar Magnesium 2 mg | Changes in the Liver Function Tests; Albumin and Total Protein | Change in albumin | -0.05 g/dL | Standard Deviation 0.22 |
| Saroglitazar Magnesium 2 mg | Changes in the Liver Function Tests; Albumin and Total Protein | Change in total protein | -0.08 g/dL | Standard Deviation 0.4 |
| Saroglitazar Magnesium 4 mg | Changes in the Liver Function Tests; Albumin and Total Protein | Change in albumin | -0.04 g/dL | Standard Deviation 0.17 |
| Saroglitazar Magnesium 4 mg | Changes in the Liver Function Tests; Albumin and Total Protein | Change in total protein | 0.09 g/dL | Standard Deviation 0.41 |
| Placebo | Changes in the Liver Function Tests; Albumin and Total Protein | Change in albumin | 0.13 g/dL | Standard Deviation 0.12 |
| Placebo | Changes in the Liver Function Tests; Albumin and Total Protein | Change in total protein | 0.27 g/dL | Standard Deviation 0.06 |
Comparison: Outcome Variable: Albuminp-value: 0.2218t-test, 2 sided
Comparison: Outcome Variable: Albuminp-value: 0.1483t-test, 2 sided
Comparison: Outcome Variable: Total Proteinp-value: 0.0839t-test, 2 sided
Comparison: Outcome Variable: Total Proteinp-value: 0.2895t-test, 2 sided
Secondary
Changes in the Liver Function Tests; Direct Bilirubin
Change in direct bilirubin
Time frame: Baseline to Week 24
Population: Modified intent-to-treat population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saroglitazar Magnesium 2 mg | Changes in the Liver Function Tests; Direct Bilirubin | -0.01 mg/dL | Standard Deviation 0.03 |
| Saroglitazar Magnesium 4 mg | Changes in the Liver Function Tests; Direct Bilirubin | -0.01 mg/dL | Standard Deviation 0.02 |
| Placebo | Changes in the Liver Function Tests; Direct Bilirubin | -0.00 mg/dL | Standard Deviation 0.02 |
Comparison: Outcome Variable: Direct Bilirubinp-value: 0.6808t-test, 2 sided
Comparison: Outcome Variable: Direct Bilirubinp-value: 0.5351t-test, 2 sided
Secondary
Changes in the Stage of Fibrosis.
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
Time frame: Baseline to Week 24
Population: Modified intent-to-treat population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saroglitazar Magnesium 2 mg | Changes in the Stage of Fibrosis. | -0.50 units on a scale | Standard Deviation 0.84 |
| Saroglitazar Magnesium 4 mg | Changes in the Stage of Fibrosis. | -0.43 units on a scale | Standard Deviation 0.79 |
| Placebo | Changes in the Stage of Fibrosis. | 0.33 units on a scale | Standard Deviation 0.58 |
p-value: 0.1705t-test, 2 sided
p-value: 0.174t-test, 2 sided
Secondary
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 (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
Time frame: Baseline to Week 24
Population: modified intent-to-treat population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Saroglitazar Magnesium 2 mg | Changes in the Stage of Steatosis, Lobular Inflammation and Ballooning. | Changes in the stage of lobular inflammation | -0.17 units on a scale | Standard Deviation 0.41 |
| Saroglitazar Magnesium 2 mg | Changes in the Stage of Steatosis, Lobular Inflammation and Ballooning. | Changes in the stage of steatosis | -0.50 units on a scale | Standard Deviation 0.55 |
| Saroglitazar Magnesium 2 mg | Changes in the Stage of Steatosis, Lobular Inflammation and Ballooning. | Changes in the stage of ballooning | -0.83 units on a scale | Standard Deviation 0.41 |
| Saroglitazar Magnesium 4 mg | Changes in the Stage of Steatosis, Lobular Inflammation and Ballooning. | Changes in the stage of lobular inflammation | -0.29 units on a scale | Standard Deviation 0.49 |
| Saroglitazar Magnesium 4 mg | Changes in the Stage of Steatosis, Lobular Inflammation and Ballooning. | Changes in the stage of steatosis | -0.71 units on a scale | Standard Deviation 0.76 |
| Saroglitazar Magnesium 4 mg | Changes in the Stage of Steatosis, Lobular Inflammation and Ballooning. | Changes in the stage of ballooning | -0.86 units on a scale | Standard Deviation 0.9 |
| Placebo | Changes in the Stage of Steatosis, Lobular Inflammation and Ballooning. | Changes in the stage of steatosis | -0.33 units on a scale | Standard Deviation 0.58 |
| Placebo | Changes in the Stage of Steatosis, Lobular Inflammation and Ballooning. | Changes in the stage of ballooning | -0.33 units on a scale | Standard Deviation 0.58 |
| Placebo | Changes in the Stage of Steatosis, Lobular Inflammation and Ballooning. | Changes in the stage of lobular inflammation | -0.67 units on a scale | Standard Deviation 0.58 |
Comparison: Outcome Variable: Steatosisp-value: 0.6845t-test, 2 sided
Comparison: Outcome Variable: Steatosisp-value: 0.4625t-test, 2 sided
Comparison: Outcome Variable: Lobular Inflammationp-value: 0.1705t-test, 2 sided
Comparison: Outcome variable: Lobular Inflammationp-value: 0.3122t-test, 2 sided
Comparison: Outcome Variable: Hepatocyte Ballooningp-value: 0.1705t-test, 2 sided
Comparison: Outcome Variable: Hepatocyte Ballooningp-value: 0.3877t-test, 2 sided
Secondary
Number of Participants Experiencing Adverse Events After Consuming Saroglitazar Magnesium 2 mg and 4 mg
Number of Participants with Adverse Events.
Time frame: Baseline to Week 24
Population: Safety Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Saroglitazar Magnesium 2 mg | Number of Participants Experiencing Adverse Events After Consuming Saroglitazar Magnesium 2 mg and 4 mg | 3 Participants |
| Saroglitazar Magnesium 4 mg | Number of Participants Experiencing Adverse Events After Consuming Saroglitazar Magnesium 2 mg and 4 mg | 5 Participants |
| Placebo | Number of Participants Experiencing Adverse Events After Consuming Saroglitazar Magnesium 2 mg and 4 mg | 2 Participants |
Secondary
Percentage of Responders Defined by the Disappearance of Steatohepatitis.
Percentage of responders defined by the disappearance of steatohepatitis
Time frame: Baseline to Week 24
Population: modified intent-to-treat population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Saroglitazar Magnesium 2 mg | Percentage of Responders Defined by the Disappearance of Steatohepatitis. | 5 Participants |
| Saroglitazar Magnesium 4 mg | Percentage of Responders Defined by the Disappearance of Steatohepatitis. | 6 Participants |
| Placebo | Percentage of Responders Defined by the Disappearance of Steatohepatitis. | 0 Participants |
p-value: 0.0476Fisher Exact
p-value: 0.0333Fisher Exact
Secondary
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.
Time frame: Baseline to Week 24
Population: modified intent-to-treat population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Saroglitazar Magnesium 2 mg | To Evaluate the Percentage of Responders in the Treatment Groups. | 4 Participants |
| Saroglitazar Magnesium 4 mg | To Evaluate the Percentage of Responders in the Treatment Groups. | 3 Participants |
| Placebo | To Evaluate the Percentage of Responders in the Treatment Groups. | 1 Participants |
p-value: 0.5238Fisher Exact
p-value: >0.9999Fisher Exact