E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Nonalcoholic steatohepatitis (NASH), is a clinical condition occurring in individuals who do not drink excessive alcohol (>20 grams/day), yet have hepatic histology which is indistinguishable from that seen with alcoholic excess. NASH has a 20% likelihood of progression to advanced disease including fibrosis, cirrhosis and its complications including liver failure and the need for a liver transplant (Angulo et al., 2002).
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E.1.1.1 | Medical condition in easily understood language |
Nonalcoholic steatohepatitis or NASH is a common, often “silent” liver disease. It resembles alcoholic liver disease, but occurs in people who drink little or no alcohol. |
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E.1.1.2 | Therapeutic area | Body processes [G] - Metabolic Phenomena [G03] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
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 |
To evaluate the effect of volixibat compared to placebo on liver histology |
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E.2.2 | Secondary objectives of the trial |
- To evaluate the safety and tolerability of volixibat compared to PBO
- To evaluate the effect of volixibat compared to PBO on hepatic steatosis (measured by MRI)
- To evaluate the effect of volixibat compared to PBO on liver histology (measured by individual NAS components and fibrosis stage)
- To evaluate the effect of volixibat compared to PBO on liver histology (measured by NASH resolution without worsening fibrosis)
- To evaluate the effect of volixibat compared to PBO on serum liver-related biochemistry
- To evaluate the effect of volixibat compared to PBO on metabolic indicators (glucose, insulin, hemoglobin A1c [HbA1c]
- To evaluate the effect of volixibat compared to PBO on serum lipids (cholesterol, HDLC, LDL-C, triglycerides) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Age 18-80 years inclusive.
2. Males and females
3. Presence of ≥ 5% steatosis on screening MRI from a centrally read radiologist performed either during the Screening period or within 6 months prior to the first visit.
4. Histologic confirmation of NASH without cirrhosis (F0-F3) from a centrally read liver biopsy performed either during the Screening period or within 6 months prior to the first visit with a NAS of ≥ 4 with a score of at least 1 in each component (steatosis, lobular inflammation, and hepatocyte ballooning).
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E.4 | Principal exclusion criteria |
1. Presence of or history of cirrhosis or evidence of decompensated liver disease (ie, ascites, variceal bleeding, etc.) or hepatocellular carcinoma.
2. History or presence of other concomitant liver disease as assessed by the investigator or determined by laboratory findings
3. Weight change ≥ 5% after qualifying liver biopsy performed.
4. Treatment with Vitamin E, thiazolidinediones, or glucagon-like peptide-1 receptors agonists (GLP1 RA) unless subject on a stable dose for 6 months prior to qualifying liver biopsy and not initiated after qualifying liver biopsy and will continue the same dosing regimen throughout study participation
5. Uncontrolled diabetes defined as HbA1c of ≥ 9.5% within 60 days prior to enrollment.
6. Serum AST > 7 times upper limit of normal (ULN) at Screening.
7. Serum ALT > 7 times ULN at Screening.
8. Elevated serum creatinine ≥ 2.0 mg/dL.
9. International normalized ratio (INR) >1.3
10. TB ≥ 2.0 x ULN at Screening (Except for documented Gilbert’s syndrome]
11. Platelet count < 130 × 10E9/L
12. Uncontrolled thyroid disease.
13. Type 1 diabetes mellitus.
14. Known history of alcohol or other substance abuse within the last year or at any time during the study based on investigator’s discretion |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the binary response indicating (yes/no) whether a subject responded at Week 48 with a reduction, of at least 2 points without worsening of fibrosis, from baseline NAS. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
•Change from Baseline to Week 48 on liver histology as measured by the individual NAS components (ballooning, inflammation, steatosis).
•Change from Baseline to Week 48 on hepatic steatosis as measured by MRI-PDFF.
•Change from Baseline to Week 48 on liver histology as measured by fibrosis stage (NASH CRN).
•Resolution of NASH (defined as total absence of ballooning [score =0], absent or mild inflammation [score 0-1], steatosis can be present [score 0-3]) without worsening of fibrosis as assessed by liver histology at Week 48.
•Change from Baseline to Week 48 on serum liver-related biochemistry
•Change from Baseline to Week 48 on metabolic indicators
•Change from Baseline to Week 48 on serum lipids |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
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) | No |
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 | 4 |
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 | 10 |
E.8.5 | The trial involves multiple Member States | No |
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 |
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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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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 | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 6 |