Non-Alcoholic Fatty Liver Disease, Nonalcoholic Steatohepatitis
Conditions
Keywords
NASH, NAFLD, Saroglitazar
Brief summary
This is a randomized, double-blind, placebo-controlled study in up to 104 patients with a diagnosis of Non-alcoholic fatty Liver disease (NAFLD) and/or Non-alcoholic steatohepatitis (NASH). The study will be conducted over a period of up to 22 weeks and will include an optional Prescreening, Screening (Days -35 to -7) Phase, a 16-week Treatment Phase following randomization on Day 1. Patients will be randomly assigned in a ratio of 1:1:1:1 to receive Saroglitazar Magnesium 1mg or 2 mg or 4 mg or matching placebo once daily in the morning before breakfast for 16 Weeks. The primary endpoint of the study is percentage change from baseline in serum Alanine transaminase (ALT) levels at Week 16 in the Saroglitazar Magnesium groups as compared to the placebo group.
Interventions
Patients randomly assigned to this group will receive Saroglitazar magnesium 1 mg tablet orally once daily for 16 weeks.
Patients randomly assigned to this group will receive Saroglitazar magnesium 2 mg tablet orally once daily for 16 weeks.
Patients randomly assigned to this group will receive Saroglitazar magnesium 4 mg tablet orally once daily for 16 weeks.
DRUGPlacebos
Patients randomly assigned to this group will receive placebo tablet orally once daily for 16 weeks.
Sponsors
Zydus Therapeutics Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Males or females, 18 to 75 years of age, with body mass index (BMI) ≥ 25 kg/m\^2. 2. Documented diagnosis of NAFLD established either by imaging (ultrasound, computed tomography \[CT\] scan or Magnetic resonance imaging \[MRI\]) or liver biopsy showing NASH or simple steatosis, within the 24 months preceding Visit 1. The diagnosis of NAFLD is made according to the American Association for the Study of Liver Diseases (AASLD) criteria (Chalasani et al. Hepatology 2012; 55:2005-2023). 3. ALT level of ≥50 U/L at Visit 1 and Visit 2 with ≤30% variance between the levels at Visit 1 and Visit 2. 4. Patient's demonstration of understanding of study requirements and treatment procedures, willingness to comply with all protocol-required evaluations; provision of written informed consent before any study specific tests or procedures are performed.
Exclusion criteria
1. 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 3 consecutive months in the 5 years preceding Visit 1 (Note: 1 unit = 12 ounces of beer, 4 ounces of wine or 1 ounce of spirits/hard liquor). 2. Presence of alternative causes of fatty liver, including: 1. Weight change \>5% within the 3 months preceding Visit 1 2. Total parenteral nutrition, starvation or protein-calorie malnutrition within the 90 days preceding Visit 1. 3. Use of drugs associated with NAFLD for more than 12 consecutive weeks in the 1 year before Visit 1, including amiodarone, tamoxifen, methotrexate, systemic glucocorticoids, anabolic steroids, tetracycline, estrogens in doses higher than used in oral contraceptives, vitamin A, L asparaginase, valproate, chloroquine or antiretroviral drugs 3. Initiation of vitamin E at doses \> 100 IU/day, or multivitamins containing \> 100 IU/day of vitamin E in the 3 months preceding Visit 1. 4. Use of drugs with potential effect on NASH such as ursodeoxycholic acid, S-adenosylmethionine (SAM-e), betaine, pentoxifylline, obeticholic acid or milk thistle in the 3 months prior to Visit 1. 5. Changing doses of statins (simvastatin, pitavastatin, pravastatin, atorvastatin, fluvastatin, lovastatin, rosuvastatin) or fibrates (clofibrate, fenofibrate) in the 3 months preceding Visit 1. 6. Use of thiazolidinediones (pioglitazone, rosiglitazone). 7. Use of drugs that are known Cytochrome P4502C8 (CYP2C8) inhibitors/substrate 8. History of bowel surgery (gastrointestinal (bariatric) surgery or undergoing evaluation for bariatric surgery for obesity, extensive small-bowel resection or orthotopic liver transplant (OLT) or listed for OLT. 9. History of other chronic liver disease (chronic hepatitis C, (HCV) infection, irrespective of their mRNA HCV assay status or active hepatitis B infection, (i.e., serum positive for hepatitis B surface antigen) or autoimmune hepatitis, cholestatic and metabolic liver diseases) or hemochromatosis 10. Patient has known cirrhosis, either based on clinical criteria or liver histology. 11. Patient with Internation Normalised Ratio (INR) \>1.3. 12. Type 1 diabetes mellitus. 13. Poorly controlled type 2 diabetes mellitus, i.e., glycosylated hemoglobin (HbA1c) \> 9%. 14. Unstable cardiovascular disease, including: 1. unstable angina, (i.e., new or worsening symptoms of coronary heart disease within the 3 months preceding Visit 1), acute coronary syndrome within the 6 months preceding Visit 1, acute myocardial infarction within the 3 months preceding Visit 1 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 Visit 1 2. history of (within 3 months preceding Visit 1) or current unstable cardiac dysrhythmias 3. uncontrolled hypertension (systolic blood pressure \[BP\] \> 160 mmHg and/or diastolic BP \> 100 mmHg) 4. stroke or transient ischemic attack within the 6 months preceding Visit 1. 15. History of myopathies or evidence of active muscle disease. 16. History of malignancy in the 5 years preceding Visit 1 and/or active neoplasm with the exception of resolved superficial nonmelanoma skin cancer. 17. Any of the following laboratory values: 1. Hemoglobin \< 9 g/dL 2. White blood cell count \< 2.5 × 103/μL 3. Neutrophil count \< 1.5 × 103/μL 4. Platelets \< 100 × 103/μL 5. Total Serum bilirubin \> 1.5 mg/dL (except in patient with known Gilbert bilirubin where Total Bilirubin up to 2.5 mg/dL is allowed), if it is \<1.5 mg/dL at screening and \>30% variance in the levels at Visit 1 and Visit 2 6. Albumin \< 3.2 g/dL 7. Serum creatinine \>1.5 mg/dL 8. Serum ALT or Aspartate aminotransferase (AST) \> 250 IU/L at Visit 1 or Visit 2 . 18. Contraindications to Saroglitazar Magnesium or has any conditions affecting the ability to evaluate the effects of Saroglitazar Magnesium. 19. Known allergy, sensitivity or intolerance to the study drug, placebo or formulation ingredients. 20. Participation in any other therapeutic clinical study within the 3 months preceding Visit 1, including participation in any other NAFLD/NASH clinical trials. 21. History of bladder disease and/or hematuria or has current hematuria except due to a urinary tract infection. 22. Illicit substance abuse within the 12 months preceding Visit 1. 23. Pregnancy-related exclusions, including: 1. Pregnant/lactating female (including a positive serum pregnancy test at Visit 1) 2. A male patient has to use a condom with spermicide, and the female partner of the male patient has to use an intrauterine device OR a diaphragm with spermicide OR oral contraceptive pills. 3. If a male patient has undergone a vasectomy, the female partner does not have to use any contraception. 4. A female patient has to use either an intrauterine device OR a diaphragm with spermicide OR oral contraceptive pills. The male partner of the female patient has to use a condom with spermicide. 5. If the female patient is surgically sterilized for at least the 6 months preceding Visit 1 or postmenopausal, defined as at least 12 months with no menses and without an alternative cause, the male partner of the female patient does not have to use any contraception. 24. 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, HIV, coronary artery disease or active gastrointestinal conditions that might interfere with drug absorption).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change From Baseline in Serum Alanine Aminotransferase (ALT) Levels at Week 16 | Baseline and Week 16 | Percentage change from baseline in serum ALT levels at Week 16 in the Saroglitazar Magnesium groups as compared to the placebo group |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients With Sustain Decrease in Serum ALT Levels | Week 16 | Proportion of patients with sustain decrease in serum ALT levels in Saroglitazar Magnesium groups as compared to the placebo group |
| Changes in Cytokeratin-18 | baseline and Week 16 | Changes in cytokeratin-18 in Saroglitazar Magnesium groups as compared to the placebo group |
| Changes in Enhanced Liver Fibrosis | baseline and Week 16 | Changes in enhanced liver fibrosis in Saroglitazar Magnesium groups as compared to the placebo group The ELF Score is a liver fibrosis score that is calculated by use of an algorithm: ELF score score = -7.412 + (ln(HA)\*0.681) + (ln(P3NP)\*0.775) + (ln(TIMP1)\*0.494). HA=hyaluronic acid concentration P3NP=procollagen 3 amino terminal peptide concentration TIMP1=tissue inhibitor matrix metalloproteinase 1 concentration. All are measured in serum. The ELF score has been reported to show good correlations with fibrosis stages in chronic liver disease, with higher ELF scores associated with higher fibrosis stages. The ELF score is hence used as a prognostic marker for disease progression: ELF score \< 9.8 : Low risk of progression, ELF score 9.8 to \< 11.3 : Moderate risk of progression and ELF score \> = 11.3 : High risk of progression |
| Change in Aspartate Aminotransferase-to-platelet Ratio Index | Baseline and Week 16 | Change in aspartate aminotransferase-to-platelet ratio index in Saroglitazar Magnesium groups as compared to the placebo group APRI was calculated as (\[AST level/AST upper limit of normal\]/ \[Platelet count 1\^09/L\]) ×100, where AST is aspartate aminotransferase. The aspartate transaminase to platelet ratio index (APRI) is used to assess the risk of liver fibrosis. Higher APRI score represents a higher risk of liver fibrosis |
| Pharmacokinetics of Saroglitazar Magnesium: Maximum Plasma Concentration (Cmax) | PK sampling timepoints: Pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, and 24 hours post-dose of Visit 7 (Week 16) | Maximum plasma concentration (Cmax) of Saroglitazar |
| Time to Reach Maximum Plasma Concentration (Tmax) | PK sampling timepoints: Pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, and 24 hours post-dose of Visit 7 (Week 16) | Time to reach maximum plasma concentration (Tmax) of saroglitazar |
| Terminal Half-life (t1/2) | PK sampling timepoints: Pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, and 24 hours post-dose of Visit 7 (Week 16) | Terminal Half-life (t1/2) of saroglitazar |
| Change in Liver Fat Content as Measured by Magnetic Resonance Imaging-derived Proton Density-fat Fraction (MRI-PDFF) | Baseline and Week 16 | Change in liver fat content as measured by magnetic resonance imaging-derived proton in Saroglitazar Magnesium groups as compared to the placebo group |
| Area Under the Curve From the Time of Dosing to the Infinity (AUC 0-inf) | PK sampling timepoints: Pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, and 24 hours post-dose of Visit 3 (Week 0) | Area under the curve from the time of dosing to the infinity (AUC 0-inf) for Saroglitazar |
| Elimination Rate Constant (λz) | PK sampling timepoints: Pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, and 24 hours post-dose of Visit 7 (Week 16) | Elimination rate constant (λz) for saroglitazar |
| Apparent Volume of Distribution (Vd/F) | PK sampling timepoints: Pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, and 24 hours post-dose of Visit 7 (Week 16) | Apparent volume of distribution (Vd/F) for Saroglitazar |
| Apparent Clearance (CL/F) | PK sampling timepoints: Pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, and 24 hours post-dose of Visit 7 (Week 16) | Apparent clearance (CL/F) for Saroglitazar |
| Change in Quality of Life Assessed by the Short-Form 36 Health Survey | baseline and 16 Week | Quality of life will be assessed by the Short-Form 36 Health Survey The SF-36 is a multi-purpose, short-form health survey with 36 questions. It yields an 8-scale profile of functional health and well-being scores (domains) as well as psychometrically based physical and mental health summary measures. The SF-36 taps 8 health concepts: physical functioning, bodily pain, physical role functioning, emotional role functioning, emotional well-being, social functioning, vitality, and general health perceptions. The 8 scales are further summarized to 2 distinct higher-ordered clusters: the PCS and mental composite t-score (MCS). The range for all 8 domains as well as for the composite t-scores is from 0 to 100 with 100 as best possible health status and 0 as worst health status. |
| Safety and Tolerability of Saroglitazar Magnesium | Baseline to Week 17 | Number of participants with adverse events |
| Area Under the Curve From the Time of Dosing to the Last Measurable Concentration (AUC0-t) | PK sampling timepoints: Pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, and 24 hours post-dose of Visit 3 (Week 0) | Area under the curve from the time of dosing to the last measurable concentration for saroglitazar |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Saroglitazar Magnesium 1 mg Saroglitazar magnesium 1 mg tablet orally once daily in the morning before breakfast for 16 weeks.
Saroglitazar magnesium 1 mg: Patients randomly assigned to this group will receive Saroglitazar magnesium 1 mg tablet orally once daily for 16 weeks. | 26 |
| Saroglitazar Magnesium 2 mg Saroglitazar magnesium 2 mg tablet orally once daily in the morning before breakfast for 16 weeks.
Saroglitazar magnesium 2 mg: Patients randomly assigned to this group will receive Saroglitazar magnesium 2 mg tablet orally once daily for 16 weeks. | 25 |
| Saroglitazar Magnesium 4 mg Saroglitazar magnesium 4 mg tablet orally once daily in the morning before breakfast for 16 weeks.
Saroglitazar magnesium 4 mg: Patients randomly assigned to this group will receive Saroglitazar magnesium 4 mg tablet orally once daily for 16 weeks. | 27 |
| Placebos Placebo tablet orally once daily in the morning before breakfast for 16 weeks.
Placebos: Patients randomly assigned to this group will receive placebo tablet orally once daily for 16 weeks. | 28 |
| Total | 106 |
Baseline characteristics
| Characteristic | Saroglitazar Magnesium 1 mg | Saroglitazar Magnesium 2 mg | Saroglitazar Magnesium 4 mg | Placebos | Total |
|---|---|---|---|---|---|
| Age, Continuous | 51.1 Years STANDARD_DEVIATION 12.89 | 47.9 Years STANDARD_DEVIATION 10.44 | 49 Years STANDARD_DEVIATION 10.97 | 48.7 Years STANDARD_DEVIATION 10.46 | 49.2 Years STANDARD_DEVIATION 11.13 |
| Body Mass Index | 33.630 kg/m^2 STANDARD_DEVIATION 4.2451 | 35.702 kg/m^2 STANDARD_DEVIATION 8.5653 | 32.489 kg/m^2 STANDARD_DEVIATION 5.1611 | 33.809 kg/m^2 STANDARD_DEVIATION 4.4599 | 33.875 kg/m^2 STANDARD_DEVIATION 5.8374 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 10 Participants | 8 Participants | 12 Participants | 13 Participants | 43 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants | 17 Participants | 15 Participants | 15 Participants | 63 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 12 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 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 | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 22 Participants | 21 Participants | 24 Participants | 24 Participants | 91 Participants |
| Sex: Female, Male Female | 13 Participants | 12 Participants | 12 Participants | 13 Participants | 50 Participants |
| Sex: Female, Male Male | 13 Participants | 13 Participants | 15 Participants | 15 Participants | 56 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 26 | 0 / 25 | 0 / 27 | 0 / 28 |
| other Total, other adverse events | 7 / 26 | 6 / 25 | 3 / 27 | 5 / 28 |
| serious Total, serious adverse events | 1 / 26 | 0 / 25 | 1 / 27 | 0 / 28 |
Outcome results
Primary
Percentage Change From Baseline in Serum Alanine Aminotransferase (ALT) Levels at Week 16
Percentage change from baseline in serum ALT levels at Week 16 in the Saroglitazar Magnesium groups as compared to the placebo group
Time frame: Baseline and Week 16
Population: Full Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saroglitazar Magnesium 1 mg | Percentage Change From Baseline in Serum Alanine Aminotransferase (ALT) Levels at Week 16 | -26.2 Percentage change | Standard Deviation 33.36 |
| Saroglitazar Magnesium 2 mg | Percentage Change From Baseline in Serum Alanine Aminotransferase (ALT) Levels at Week 16 | -27.0 Percentage change | Standard Deviation 26.52 |
| Saroglitazar Magnesium 4 mg | Percentage Change From Baseline in Serum Alanine Aminotransferase (ALT) Levels at Week 16 | -44.9 Percentage change | Standard Deviation 26.26 |
| Placebo | Percentage Change From Baseline in Serum Alanine Aminotransferase (ALT) Levels at Week 16 | 2.6 Percentage change | Standard Deviation 32.06 |
p-value: 0.0002ANCOVA
p-value: 0.0001ANCOVA
p-value: <0.0001ANCOVA
Secondary
Apparent Clearance (CL/F)
Apparent clearance (CL/F) for Saroglitazar
Time frame: PK sampling timepoints: Pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, and 24 hours post-dose of Visit 7 (Week 16)
Population: PK population For Saroglitazar 4 mg, one subject was not considered for calculation of CL/F as adjusted R square was observed \<0.8000 and AUC\_%Extrap\_obs\>20%. Hence, N=07 instead of 08 for CL/F.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saroglitazar Magnesium 1 mg | Apparent Clearance (CL/F) | 5969.472 mL/hour | Standard Deviation 2502.313 |
| Saroglitazar Magnesium 2 mg | Apparent Clearance (CL/F) | 8030.060 mL/hour | Standard Deviation 2356.62 |
| Saroglitazar Magnesium 4 mg | Apparent Clearance (CL/F) | 6972.059 mL/hour | Standard Deviation 1890.09 |
Secondary
Apparent Volume of Distribution (Vd/F)
Apparent volume of distribution (Vd/F) for Saroglitazar
Time frame: PK sampling timepoints: Pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, and 24 hours post-dose of Visit 7 (Week 16)
Population: PK population For Saroglitazar 4 mg, one subject was not considered for calculation of Vd/F as adjusted R square was observed \<0.8000 and AUC\_%Extrap\_obs\>20%. Hence, N=07 instead of 08 for Vd/F
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saroglitazar Magnesium 1 mg | Apparent Volume of Distribution (Vd/F) | 49788.200 mL | Standard Deviation 18040.188 |
| Saroglitazar Magnesium 2 mg | Apparent Volume of Distribution (Vd/F) | 81341.167 mL | Standard Deviation 72030.406 |
| Saroglitazar Magnesium 4 mg | Apparent Volume of Distribution (Vd/F) | 53772.143 mL | Standard Deviation 17575.77 |
Secondary
Area Under the Curve From the Time of Dosing to the Infinity (AUC 0-inf)
Area under the curve from the time of dosing to the infinity (AUC 0-inf) for Saroglitazar
Time frame: PK sampling timepoints: Pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, and 24 hours post-dose of Visit 3 (Week 0)
Population: PK population For Saroglitazar 4 mg, one subject was not considered for calculation of AUC 0-inf as adjusted R square was observed \<0.8000 and AUC\_%Extrap\_obs\>20%. Hence, N=07 instead of 08 for AUC 0-inf
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saroglitazar Magnesium 1 mg | Area Under the Curve From the Time of Dosing to the Infinity (AUC 0-inf) | 167.735 hr*ng/mL | Standard Deviation 45.322 |
| Saroglitazar Magnesium 2 mg | Area Under the Curve From the Time of Dosing to the Infinity (AUC 0-inf) | 305.532 hr*ng/mL | Standard Deviation 203.074 |
| Saroglitazar Magnesium 4 mg | Area Under the Curve From the Time of Dosing to the Infinity (AUC 0-inf) | 652.497 hr*ng/mL | Standard Deviation 169.565 |
Secondary
Area Under the Curve From the Time of Dosing to the Last Measurable Concentration (AUC0-t)
Area under the curve from the time of dosing to the last measurable concentration for saroglitazar
Time frame: PK sampling timepoints: Pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, and 24 hours post-dose of Visit 3 (Week 0)
Population: PK population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saroglitazar Magnesium 1 mg | Area Under the Curve From the Time of Dosing to the Last Measurable Concentration (AUC0-t) | 171.064 hr*ng/mL | Standard Deviation 45.818 |
| Saroglitazar Magnesium 2 mg | Area Under the Curve From the Time of Dosing to the Last Measurable Concentration (AUC0-t) | 301.227 hr*ng/mL | Standard Deviation 202.061 |
| Saroglitazar Magnesium 4 mg | Area Under the Curve From the Time of Dosing to the Last Measurable Concentration (AUC0-t) | 667.646 hr*ng/mL | Standard Deviation 175.024 |
Secondary
Change in Aspartate Aminotransferase-to-platelet Ratio Index
Change in aspartate aminotransferase-to-platelet ratio index in Saroglitazar Magnesium groups as compared to the placebo group APRI was calculated as (\[AST level/AST upper limit of normal\]/ \[Platelet count 1\^09/L\]) ×100, where AST is aspartate aminotransferase. The aspartate transaminase to platelet ratio index (APRI) is used to assess the risk of liver fibrosis. Higher APRI score represents a higher risk of liver fibrosis
Time frame: Baseline and Week 16
Population: Full Analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saroglitazar Magnesium 1 mg | Change in Aspartate Aminotransferase-to-platelet Ratio Index | -0.3 units on a scale | Standard Deviation 0.56 |
| Saroglitazar Magnesium 2 mg | Change in Aspartate Aminotransferase-to-platelet Ratio Index | -0.2 units on a scale | Standard Deviation 0.51 |
| Saroglitazar Magnesium 4 mg | Change in Aspartate Aminotransferase-to-platelet Ratio Index | -0.3 units on a scale | Standard Deviation 0.47 |
| Placebo | Change in Aspartate Aminotransferase-to-platelet Ratio Index | 0.1 units on a scale | Standard Deviation 0.73 |
p-value: 0.0045ANCOVA
p-value: 0.0026ANCOVA
p-value: 0.0004ANCOVA
Secondary
Change in Liver Fat Content as Measured by Magnetic Resonance Imaging-derived Proton Density-fat Fraction (MRI-PDFF)
Change in liver fat content as measured by magnetic resonance imaging-derived proton in Saroglitazar Magnesium groups as compared to the placebo group
Time frame: Baseline and Week 16
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saroglitazar Magnesium 1 mg | Change in Liver Fat Content as Measured by Magnetic Resonance Imaging-derived Proton Density-fat Fraction (MRI-PDFF) | 0.53 percentage of Liver fat | Standard Deviation 5.228 |
| Saroglitazar Magnesium 2 mg | Change in Liver Fat Content as Measured by Magnetic Resonance Imaging-derived Proton Density-fat Fraction (MRI-PDFF) | -0.36 percentage of Liver fat | Standard Deviation 4.297 |
| Saroglitazar Magnesium 4 mg | Change in Liver Fat Content as Measured by Magnetic Resonance Imaging-derived Proton Density-fat Fraction (MRI-PDFF) | -4.21 percentage of Liver fat | Standard Deviation 6.231 |
| Placebo | Change in Liver Fat Content as Measured by Magnetic Resonance Imaging-derived Proton Density-fat Fraction (MRI-PDFF) | -0.28 percentage of Liver fat | Standard Deviation 5.409 |
p-value: 0.5681ANCOVA
p-value: 0.4487ANCOVA
p-value: 0.0021ANCOVA
Secondary
Change in Quality of Life Assessed by the Short-Form 36 Health Survey
Quality of life will be assessed by the Short-Form 36 Health Survey The SF-36 is a multi-purpose, short-form health survey with 36 questions. It yields an 8-scale profile of functional health and well-being scores (domains) as well as psychometrically based physical and mental health summary measures. The SF-36 taps 8 health concepts: physical functioning, bodily pain, physical role functioning, emotional role functioning, emotional well-being, social functioning, vitality, and general health perceptions. The 8 scales are further summarized to 2 distinct higher-ordered clusters: the PCS and mental composite t-score (MCS). The range for all 8 domains as well as for the composite t-scores is from 0 to 100 with 100 as best possible health status and 0 as worst health status.
Time frame: baseline and 16 Week
Population: Full Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saroglitazar Magnesium 1 mg | Change in Quality of Life Assessed by the Short-Form 36 Health Survey | -1.7 units on a scale | Standard Deviation 7.24 |
| Saroglitazar Magnesium 2 mg | Change in Quality of Life Assessed by the Short-Form 36 Health Survey | -2.2 units on a scale | Standard Deviation 7.57 |
| Saroglitazar Magnesium 4 mg | Change in Quality of Life Assessed by the Short-Form 36 Health Survey | -3.8 units on a scale | Standard Deviation 10.77 |
| Placebo | Change in Quality of Life Assessed by the Short-Form 36 Health Survey | -1.0 units on a scale | Standard Deviation 6.16 |
p-value: 0.2387ANCOVA
p-value: 0.1496ANCOVA
p-value: 0.0445ANCOVA
Secondary
Changes in Cytokeratin-18
Changes in cytokeratin-18 in Saroglitazar Magnesium groups as compared to the placebo group
Time frame: baseline and Week 16
Population: full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saroglitazar Magnesium 1 mg | Changes in Cytokeratin-18 | -3.0 U/L | Standard Deviation 693.75 |
| Saroglitazar Magnesium 2 mg | Changes in Cytokeratin-18 | -330.3 U/L | Standard Deviation 590.37 |
| Saroglitazar Magnesium 4 mg | Changes in Cytokeratin-18 | -64.1 U/L | Standard Deviation 303.59 |
| Placebo | Changes in Cytokeratin-18 | 97.4 U/L | Standard Deviation 437.1 |
p-value: 0.2241ANCOVA
p-value: 0.0304ANCOVA
p-value: 0.0595ANCOVA
Secondary
Changes in Enhanced Liver Fibrosis
Changes in enhanced liver fibrosis in Saroglitazar Magnesium groups as compared to the placebo group The ELF Score is a liver fibrosis score that is calculated by use of an algorithm: ELF score score = -7.412 + (ln(HA)\*0.681) + (ln(P3NP)\*0.775) + (ln(TIMP1)\*0.494). HA=hyaluronic acid concentration P3NP=procollagen 3 amino terminal peptide concentration TIMP1=tissue inhibitor matrix metalloproteinase 1 concentration. All are measured in serum. The ELF score has been reported to show good correlations with fibrosis stages in chronic liver disease, with higher ELF scores associated with higher fibrosis stages. The ELF score is hence used as a prognostic marker for disease progression: ELF score \< 9.8 : Low risk of progression, ELF score 9.8 to \< 11.3 : Moderate risk of progression and ELF score \> = 11.3 : High risk of progression
Time frame: baseline and Week 16
Population: Full Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saroglitazar Magnesium 1 mg | Changes in Enhanced Liver Fibrosis | -0.2 units on a scale | Standard Deviation 0.78 |
| Saroglitazar Magnesium 2 mg | Changes in Enhanced Liver Fibrosis | -0.3 units on a scale | Standard Deviation 0.86 |
| Saroglitazar Magnesium 4 mg | Changes in Enhanced Liver Fibrosis | -0.3 units on a scale | Standard Deviation 0.72 |
| Placebo | Changes in Enhanced Liver Fibrosis | 0.4 units on a scale | Standard Deviation 0.78 |
p-value: 0.0449ANCOVA
p-value: 0.0053ANCOVA
p-value: 0.0036ANCOVA
Secondary
Elimination Rate Constant (λz)
Elimination rate constant (λz) for saroglitazar
Time frame: PK sampling timepoints: Pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, and 24 hours post-dose of Visit 7 (Week 16)
Population: PK population For Saroglitazar 4 mg, one subject was not considered for calculation of Kel as adjusted R square was observed \<0.8000 and AUC\_%Extrap\_obs\>20%. Hence, N=07 instead of 08 for Kel
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saroglitazar Magnesium 1 mg | Elimination Rate Constant (λz) | 0.119 per hour | Standard Deviation 0.027 |
| Saroglitazar Magnesium 2 mg | Elimination Rate Constant (λz) | 0.129 per hour | Standard Deviation 0.047 |
| Saroglitazar Magnesium 4 mg | Elimination Rate Constant (λz) | 0.136 per hour | Standard Deviation 0.035 |
Secondary
Pharmacokinetics of Saroglitazar Magnesium: Maximum Plasma Concentration (Cmax)
Maximum plasma concentration (Cmax) of Saroglitazar
Time frame: PK sampling timepoints: Pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, and 24 hours post-dose of Visit 7 (Week 16)
Population: PK population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saroglitazar Magnesium 1 mg | Pharmacokinetics of Saroglitazar Magnesium: Maximum Plasma Concentration (Cmax) | 65.034 ng/mL | Standard Deviation 17.579 |
| Saroglitazar Magnesium 2 mg | Pharmacokinetics of Saroglitazar Magnesium: Maximum Plasma Concentration (Cmax) | 98.995 ng/mL | Standard Deviation 77.189 |
| Saroglitazar Magnesium 4 mg | Pharmacokinetics of Saroglitazar Magnesium: Maximum Plasma Concentration (Cmax) | 219.475 ng/mL | Standard Deviation 111.521 |
Secondary
Proportion of Patients With Sustain Decrease in Serum ALT Levels
Proportion of patients with sustain decrease in serum ALT levels in Saroglitazar Magnesium groups as compared to the placebo group
Time frame: Week 16
Population: Full Analysis set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Saroglitazar Magnesium 1 mg | Proportion of Patients With Sustain Decrease in Serum ALT Levels | 22 Participants |
| Saroglitazar Magnesium 2 mg | Proportion of Patients With Sustain Decrease in Serum ALT Levels | 22 Participants |
| Saroglitazar Magnesium 4 mg | Proportion of Patients With Sustain Decrease in Serum ALT Levels | 26 Participants |
| Placebo | Proportion of Patients With Sustain Decrease in Serum ALT Levels | 14 Participants |
p-value: 0.007Chi-squared
p-value: 0.0031Chi-squared
p-value: 0.0001Chi-squared
Secondary
Safety and Tolerability of Saroglitazar Magnesium
Number of participants with adverse events
Time frame: Baseline to Week 17
Population: Safety Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Saroglitazar Magnesium 1 mg | Safety and Tolerability of Saroglitazar Magnesium | 13 participants |
| Saroglitazar Magnesium 2 mg | Safety and Tolerability of Saroglitazar Magnesium | 13 participants |
| Saroglitazar Magnesium 4 mg | Safety and Tolerability of Saroglitazar Magnesium | 14 participants |
| Placebo | Safety and Tolerability of Saroglitazar Magnesium | 19 participants |
Secondary
Terminal Half-life (t1/2)
Terminal Half-life (t1/2) of saroglitazar
Time frame: PK sampling timepoints: Pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, and 24 hours post-dose of Visit 7 (Week 16)
Population: PK population For Saroglitazar 4 mg, one subject was not considered for calculation of Half-life as adjusted R square was observed \<0.8000 and AUC\_%Extrap\_obs\>20%. Hence, N=07 instead of 08 for Half-life
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saroglitazar Magnesium 1 mg | Terminal Half-life (t1/2) | 6.040 hour | Standard Deviation 1.314 |
| Saroglitazar Magnesium 2 mg | Terminal Half-life (t1/2) | 6.597 hour | Standard Deviation 4.217 |
| Saroglitazar Magnesium 4 mg | Terminal Half-life (t1/2) | 5.429 hour | Standard Deviation 1.509 |
Secondary
Time to Reach Maximum Plasma Concentration (Tmax)
Time to reach maximum plasma concentration (Tmax) of saroglitazar
Time frame: PK sampling timepoints: Pre-dose (0.0), 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, and 24 hours post-dose of Visit 7 (Week 16)
Population: PK population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Saroglitazar Magnesium 1 mg | Time to Reach Maximum Plasma Concentration (Tmax) | 0.920 hours |
| Saroglitazar Magnesium 2 mg | Time to Reach Maximum Plasma Concentration (Tmax) | 1.500 hours |
| Saroglitazar Magnesium 4 mg | Time to Reach Maximum Plasma Concentration (Tmax) | 0.990 hours |