| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Primary biliary Cholangitis
|
|
| E.1.1.1 | Medical condition in easily understood language |
| Primary biliary cholangitis or primary biliary cirrhosis |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 27.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10080429 |
| E.1.2 | Term | Primary biliary cholangitis |
| E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To demonstrate superiority of Saroglitazar Magnesium Optimal Dose (1 or 2 mg) dosed once daily relative to Placebo with respect to biochemical response based on the composite endpoints of ALP and total bilirubin at Week 52 in subjects with PBC. |
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate the effect of Saroglitazar Magnesium 1 mg/Optimal Dose (1 or 2 mg)and Saroglitazar Magnesium 2 mg/Optimal Dose (1 or 2 mg) relative to Placebo with respect to biochemical response based on the composite endpoints of ALP and total bilirubin at Weeks 4, 8, 16, and 24.
2. To evaluate the effect of Saroglitazar Magnesium Optimal Dose (1 or 2 mg) relative to Placebo with respect to change from baseline in ALP at Weeks 24 and 52.
3. To evaluate the effect of Saroglitazar Magnesium Optimal Dose (1 or 2 mg) relative to Placebo with respect to improvement in liver stiffness measurement (LSM) of at least 25% at Weeks 24 and 52 relative to baseline assessed by FibroScan®.
4. To evaluate the effect of Saroglitazar Magnesium 1 mg/Optimal Dose (1 or 2 mg) and Saroglitazar Magnesium 2 mg/Optimal Dose (1 or 2 mg) relative to Placebo at Weeks 16, 24, and 52.
........... |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Males or females, between 18 and 75 years of age, both inclusive at screening.
2. Subjects on ursodeoxycholic acid (UDCA) for at least 12 months at a therapeutic dose (at least 13 mg/kg per day) and a stable dose for 6 months prior to Screening Visit and having ALP ≥ 1.67 x ULN.
OR
Subjects who are unable to tolerate UDCA and did not receive UDCA for at least 3 months prior to the date of screening and having ALP ≥ 1.67 x ULN.
3. History of confirmed PBC diagnosis, based on American Association for the Study of Liver Disease [AASLD] and European Association for Study of the Liver [EASL] Practice Guidelines, as demonstrated by the presence of at least ≥ 2 of the following 3 diagnostic factors:
-History of elevated ALP levels for at least 6 months prior to screening
-The subjects should have positive anti-mitochondrial antibodies (AMA) titer OR if AMA is negative or in low titer (< 1:80), then the subjects should have PBC specific antibodies (anti-GP210 and/or anti-SP100 and/or antibodies against the major M2 components [PDC-E2, 2-oxo-glutaric acid dehydrogenase complex])
-Liver biopsy consistent with PBC
4. ALP ≥ 1.67 x ULN at both Visits 1 and 2 and with < 30% variance between the levels from Visit 1 to Visit 2
5. Total bilirubin < 2 x ULN at screening (Visit 1)
6. Must provide written informed consent and agree to comply with the trial protocol. |
|
| E.4 | Principal exclusion criteria |
1.Consumption of 2 standard alcohol drinks per day if male and 1 standard alcohol drink per day if female for at least 3 consecutive months (12 consecutive weeks) within 5 year before screening. 2.History or presence of other concomitant liver diseases at screening: a.Chronic hepatitis B or C virus (HBV, HCV) infection. b.Primary sclerosing cholangitis (PSC). c.Alcoholic liver disease. d.Autoimmune hepatitis (AIH) indicative of PBC with overlap syndrome. e.Hemochromatosis. f.Non-alcoholic steatohepatitis (NASH) on historical biopsy. 3.Cirrhosis with complications, including history or presence of: spontaneous bacterial peritonitis, hepatocellular carcinoma, encephalopathy, known large esophageal varices or history of variceal bleeding and active or history of hepatorenal syndrome at screening. 4.Clinically silent compensated cirrhosis (at screening), defined as (a) nodular liver contour by abdominal imaging with at least one sign of liver dysfunction (> ULN INR or < LLN serum albumin); or (b) prolonged INR (> ULN) and diminished albumin (< LLN); or (c) platelet count <140x109/L with INR > ULN or serum albumin < LLN. 5.Medical conditions that may cause non-hepatic increases in ALP (e.g., Paget's disease) or which may diminish life expectancy to < 2 years, including known cancers. 6.Use of thiazolidinediones or fibrates (within 12 weeks prior to screening) 7.Use of obeticholic acid (OCA), azathioprine, cyclosporine, methotrexate, mycophenolate, pentoxifylline, budesonide and other systemic corticosteroids (Note: Prednisone dose should not be more than 10 mg per day); potentially hepatotoxic drugs (including α-methyl-dopa, sodium valproic acid, isoniazid, or nitrofurantoin) (within 12 weeks prior to screening) 8.Use of drugs that are known cytochromes P2C8 (CYP2C8) inhibitors/substrate within 4 weeks prior to screening (refer to Appendix 7 for List of Known CYP2C8 Inhibitors/Substrate).
9. History of bowel surgery (gastrointestinal [bariatric] surgery in the preceding 1 year or undergoing evaluation for gastrointestinal surgery (bariatric surgery for obesity, extensive small-bowel resection) or orthotopic liver transplant (OLT) or listed for OLT. 10.Type 1 diabetes mellitus
11. Unstable cardiovascular disease, including: a. Unstable angina, (i.e., new or worsening symptoms of coronary heart disease in the 12 weeks before screening and throughout the Screening Period), acute coronary syndrome in the 24 weeks before screening and throughout the Screening Period, acute myocardial infarction in the 12 weeks before screening and throughout the Screening Period or heart failure of New York Heart Association class (III to IV) or worsening congestive heart failure, or coronary artery intervention, in the 24 weeks before screening and throughout the Screening Period. b. History/current unstable cardiac dysrhythmias. c. Uncontrolled hypertension at screening. d. Stroke or transient ischemic attack in the 24 weeks before screening. 12. History of intracranial hemorrhage, arteriovenous malformation, bleeding disorder, coagulation disorders, or screening blood tests that, in the opinion of the Investigator, indicate altered coagulability (e.g., PT, INR, aPTT) at screening. 13. An uncontrolled thyroid disorder a. Uncontrolled hyperthyroidism: defined as any history of hyperthyroidism that has either not been treated with either radioactive iodine and/or surgery or that has been treated with radioactive iodine and/or surgery, but has required ongoing continuous or intermittent use of thyroid hormone synthesis inhibitors (i.e., methimazole or propylthiouracil) in the 24 weeks before screening b. Uncontrolled hypothyroidism: defined as initiation of thyroid hormone replacement therapy or dose adjustment of replacement therapy in the 12 weeks before screening. 14. History of myopathies or evidence of active muscle disease demonstrated by CPK ≥ 5 x ULN at screening. 15. Subjects whose ALT, AST, or ALP exceeds by more than 50% on Visit 2 reading compared to Visit 1. Note: If the ALT, AST or ALP values on Visit 2 exceed by more than 50% from Visit 1, then a third value will be measured (within 1- 2 weeks) to assess for the trend. If the third value shows continued increase ≥ 10%, then subject is considered ineligible for randomization.
16. Any of the following laboratory values at screening: a. Platelets < 100 × 109/L b. Albumin < 3.2 g/dL c. eGFR < 60 mL/min/1.73 m2 d. ALP > 10 x ULN e. ALT or AST > 250 U/L. 17. Participation in another interventional clinical study and receipt of any other investigational medication (within 12 weeks prior to randomization up to end of study). 18. History of malignancy in the past 5 years and/or active neoplasm with the exception of resolved superficial non-melanoma skin cancer. 19. Contraindications to Saroglitazar Magnesium or has any conditions affecting the ability to evaluate the effects of Saroglitazar Magnesium...... |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of subjects with biochemical response based on the composite endpoints of ALP and total bilirubin [ALP < 1.67 x ULN, ≥ 15% decrease in ALP relative to baseline, and total bilirubin ≤ ULN or direct bilirubin ≤ ULN in patients with known Gilbert’s syndrome] at Week 52. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Proportion of subjects with biochemical response based on the composite endpoints of ALP and total bilirubin [ALP < 1.67 x ULN, ≥ 15% decrease in ALP, and total bilirubin ≤ ULN or direct bilirubin ≤ ULN in patients with known Gilbert’s syndrome] at Weeks 4, 8, 16, and 24.
-Proportion of subjects with ALP improvement of at least 15%, 30%, 40%, and 50% at Weeks 24 and 52.
-Change and percent change from baseline in ALP at Weeks 24 and 52.
-Proportion of subjects with complete normalization of ALP at Weeks 24 and 52.
-Proportion of subjects with decrease in LSM of at least 25% from baseline to Weeks 24 and 52.
-Change from baseline in liver enzyme parameters (ALT, AST, GGT, total bilirubin and albumin) at Weeks 16, 24, and 52.
-Change from baseline in lipid parameters (TG, LDL-C, HDL-C, VLDL-C, total cholesterol, and non-HDL-C) at Weeks 24 and 52.
-Change from baseline in serum bile acids at Weeks 24 and 52.
-Change from baseline in 5-D itch scale at Weeks 4, 8, 16, 24, and 52.
-Change from baseline in quality of life (PBC 40) questionnaire domains at Weeks 16, 24 and 52.
-Change from baseline in PGIC scale at Weeks 4, 8, 16, 24, and 52.
-Change from baseline in PGTB scale at Weeks 4, 8, 16, 24, and 52.
-Change from baseline in PGIWIS scale at Weeks 4, 8, 16, 24, and 52.
-Frequency and severity of AEs and SAEs
-Frequency of AE of special interest (AESI): drug-induced liver injury (DILI)
-Clinical laboratory testing (hematology, biochemistry, and urinalysis)
-Vital signs
-Body weight
-12-lead electrocardiogram (ECG)
-Physical examination |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Weeks 4, 8, 16, 24, and 52 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| United States |
| Iceland |
| Italy |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| LVLS |
| Last visit last patient |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 15 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 15 |
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