E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Non-alcoholic steatohepatitis |
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E.1.1.1 | Medical condition in easily understood language |
Non-alcoholic steatohepatitis (NASH) |
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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 | 20.1 |
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 |
To compare the effect of semaglutide subcutaneous (s.c.) once daily versus placebo on histological resolution of non-alcoholic steatohepatitis (NASH). |
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E.2.2 | Secondary objectives of the trial |
1. To investigate the dose-response relationship of three dose levels of semaglutide s.c. once daily (0.1 mg/day, 0.2 mg/day and 0.4 mg/day) on histological resolution of NASH.
2. To compare the effects of semaglutide s.c. once daily to placebo on liver-related histological parameters and biomarkers of NASH disease.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Informed consent obtained before any trial-related activities. Trial-related activities are any procedures that are carried out as part of the trial, including activities to determine suitability for the trial except for protocol described pre-screening activities which require a separate informed consent.
2. Male or female, aged 18-75 years (both inclusive) (for Japan: male or female aged 20-75 years (both inclusive) at the time of signing informed consent.
3. Histologic evidence of NASH based on central pathologist evaluation of a liver biopsy obtained up to 21 weeks before screening.
4. A histological NAS > = 4 with a score of 1 or more in each subcomponent of the score based on central pathologist evaluation.
5. NASH fibrosis stage 1, 2 or 3 according to the NASH CRN fibrosis staging system based on central pathologist evaluation. |
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E.4 | Principal exclusion criteria |
1. Known or suspected abuse of alcohol (> 20 g/day for women or > 30 g/day for men), alcohol dependence* or narcotics. (* = assessed by the Alcohol Use Disorders Identification Test (AUDIT questionnaire)).
2. Diagnosis of type 1 diabetes according to medical records.
3. HbA1c > 10% at screening.
4. History or presence of pancreatitis (acute or chronic).
5. Calcitonin ≥ 50 ng/L at screening.
6. Family or personal history of multiple endocrine neoplasia type 2 or medullary thyroid carcinoma. Family is defined as a first degree relative.
7. Body Mass Index (BMI) ≤ 25.0 kg/sqm at the screening visit (visit 1).
8. Female who is pregnant, breast-feeding or intends to become pregnant or is of childbearing potential and not using an adequate contraceptive method (adequate contraceptive measures as required by local regulation or practice).
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E.5 End points |
E.5.1 | Primary end point(s) |
NASH resolution without worsening of fibrosis (yes/no) |
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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) |
1. At least one stage of liver fibrosis improvement with no worsening of NASH (yes/no) (worsening defined as an increase of at least one stage of either lobular inflammation or hepatocyte ballooning according to NASH clinical research network (CRN) criteria).
2. Change in non-alcoholic fatty liver disease (NAFLD) activity score (NAS) (0-8)
3. Change in stage of fibrosis according to the Kleiner fibrosis classification (0-4)
4. Change in activity component of steatosis-activity-fibrosis (SAF) score (0-4)
5. Change in fasting plasma glucose (FPG)
6. Change in glycosylated haemoglobin A1c (HbA1c)
7. Change in serum enhanced liver fibrosis (ELF)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. After 72 weeks
2. – 7. From baseline to week 72
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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 | 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 | 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 | 6 |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 47 |
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 |
European Union |
Japan |
Russian Federation |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
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 | 7 |
E.8.9.1 | In the Member State concerned days | 6 |
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 | 7 |
E.8.9.2 | In all countries concerned by the trial days | 6 |