E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Compensated Cirrhosis due to Nonalcoholic Steatohepatitis |
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E.1.1.1 | Medical condition in easily understood language |
Compensated Cirrhosis due to Nonalcoholic Steatohepatitis |
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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 | 24.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10053219 |
E.1.2 | Term | Non-alcoholic steatohepatitis |
E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
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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 |
Primary Objectives Assessed at the End of the Double-Blind Phase: The primary objectives are to evaluate the effects of OCA treatment compared with placebo on: • Histological improvement in fibrosis by assessing the percentage of subjects with improvement in fibrosis by at least 1 stage with no worsening of NASH defined as no increase in hepatocellular ballooning or lobular inflammation using the NASH CRN scoring system, from Baseline to the end of the Double-Blind Phase. Primary Objectives Assessed at the End of the Open-Label Extension (OLE) • To evaluate and summarize the longer-term safety and tolerability of OCA treatment • To summarize the effects of OCA treatment on the occurrence of all-cause mortality and liver-related clinical outcomes for the adjudicated events (clinical outcomes composite endpoint) described in the protocol.
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E.2.2 | Secondary objectives of the trial |
Secondary Objectives Assessed at the End of the Double-Blind Phase The secondary objectives are to evaluate the effects of OCA treatment compared with placebo on: • Resolution of NASH defined as overall histopathological interpretation of 1) "no fatty liver disease" or 2) "fatty liver disease (simple or isolated steatosis) without steatohepatitis" AND a NAS of 0 for ballooning and 0-1 for inflammation, using the NASH CRN scoring system, from Baseline to the end of the Double-Blind Phase • Resolution of NASH based on pathologist's overall histopathologic interpretation of the presence or absence of definite NASH from Baseline to the end of the Double-Blind Phase • Histological changes in fibrosis status, including: (1) improvement or (2) no change, from Baseline to the end of the Double-Blind Phase using the NASH CRN scoring system • Occurrence of all-cause mortality and liver-related clinical outcomes for the adjudicated events described in the protocol. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects with a confirmed diagnosis of NASH and a fibrosis score of 4 based upon the NASH CRN scoring system determined by central reading.
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E.4 | Principal exclusion criteria |
1. Current or past history of a clinically evident hepatic decompensation such as clinically significant ascites, hepatic encephalopathy (HE), or variceal bleeding. 2. Current or past history of CP score ≥7 points 3. MELD score >12 4. ALT ≥5× ULN 5. Calculated creatinine clearance <60 mL/min using Cockcroft-Gault method 6. Hemoglobin A1c ≥9.5% 7. Evidence of other known forms of chronic liver disease such as alcoholic liver disease, hepatitis B, hepatitis C, PBC, PSC, autoimmune hepatitis, Wilson disease, iron overload, Alpha-1-antitrypsin deficiency, drug-induced liver injury, Known or suspected HCC 8. History of liver transplant, current placement on a liver transplant list
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E.5 End points |
E.5.1 | Primary end point(s) |
Improvement in fibrosis by at least 1 stage with no worsening of NASH defined as no increase in hepatocellular ballooning or lobular inflammation using NASH CRN scoring system, from Baseline to the end of the Double-Blind Phase |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Baseline to the end of the Double-Blind Phase |
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E.5.2 | Secondary end point(s) |
- No fatty liver disease or fatty liver disease (simple or isolated steatosis) without steatohepatitis AND a NAS of 0 for ballooning and 0-1 for inflammation, using the NASH CRN scoring system, from Baseline to the end of the Double-Blind Phase; - NASH resolution based on pathologist's overall histopathologic interpretation of the presence or absence of definite NASH from Baseline to the end of the Double-Blind Phase; - Change in NASH CRN scoring system from Baseline to the end of the Double-Blind Phase; - Occurrence of any of the following adjudicated events: death (all cause); liver transplant; MELD score ≥15; worsening of CP score by at least 2 points; hospitalization (as defined by a stay of ≥24 hours) for variceal bleed, HE (as defined by a West Haven score of ≥2) or SBP (confirmed by diagnostic paracentesis); ascites secondary to cirrhosis and requiring medical intervention (eg, diuretics or paracentesis); HCC confirmed by 2 complementary imaging modalities unless already confirmed by biopsy
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Baseline to the end of the Double-Blind Phase |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
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) | No |
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
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 12 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 68 |
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 |
Australia |
Canada |
Germany |
Hungary |
New Zealand |
Poland |
Spain |
Ukraine |
United Kingdom |
United States |
France |
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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
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Last Visit of Last Subject |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 13 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 4 |