| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| non-alcoholic steatohepatitis |
|
| E.1.1.1 | Medical condition in easily understood language |
| non-alcoholic steatohepatitis |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| 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 |
|
| 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 |
This trial will characterize the dose response curve for BI 456906 in patients with NASH
(NAS ≥ 4, fibrosis F1-F3) by assessing three doses and placebo. The response is the
proportion of patients with improvement from baseline in liver histological findings after 48
weeks. |
|
| E.2.2 | Secondary objectives of the trial |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Rationale: a sub-study for exploratory assessment of liver biopsy specimens will be implemented in France, Germany, Japan, Poland, and the USA.
Local Amendment to the Clinical Trial Protocol, version 1.0, dated 16 Nov 2021.
Objective: The aim of this sub-study is to evaluate results from two histological readings in addition to the main study and to compare these evaluations. |
|
| E.3 | Principal inclusion criteria |
- Male or female patients ≥ 18 years and ≤ 80 years of age at time of consent.
- Diagnosis of NASH (NAS ≥ 4, with at least 1 point in inflammation and ballooning each) and fibrosis stage F1–F3 proven by a biopsy conducted during the screening period or by a historical biopsy conducted within the last 6 months prior to randomization and stable body weight defined as less than 5% self-reported change in body weight between the historical biopsy and randomization, if a historical biopsy is used.
- Liver fat fraction ≥ 8% measured by MRI-PDFF and liver stiffness > 6.0 kPa measured by FibroScan® at Visit 1 (if biopsy is scheduled during the screening period MRI-PDFF and FibroScan® assessments have to be performed prior to the biopsy). However, the diagnosis of NASH and fibrosis at liver biopsy (including historical biopsy) is the primary assessment to establish patient eligibility.
- Patients willing and able to undergo liver biopsies per protocol as judged by the Investigator.
- BMI ≥ 23 kg/m2 and a body weight ≥ 70 kg at screening visit.
- Signed and dated written informed consent in accordance with ICH-GCP and local legislation prior to admission to the trial.
- Women of childbearing potential (WOCBP) must be willing and able to use two forms of effective contraception where at least one form is highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly. A list of contraception methods meeting these criteria is provided in the patient information. |
|
| E.4 | Principal exclusion criteria |
- Current or history of significant alcohol consumption (defined as intake of > 210 g/ week in males and > 140 g/ week in females on average over a consecut ive period of more than 3 months) or inability to reliably quantify alcohol consumption based on Investigator judgement within the last 5 years.
- Intake of medications historically associated with liver injury, hepatic steatosis or steatohepatitis within 12 weeks prior to Visit 1. Intake of restricted medications or any medications considered likely to interfere with the safe conduct of the trial
- History of other forms of chronic liver disease (e.g. viral hepatitis, autoimmune liver disease, primary biliary sclerosis, primary sclerosing cholangitis, Wilson's disease, hemochromatosis, A1At deficiency, history of liver transplantation). Hepatitis B and C testing will be done at Visit 1. Patients with positive HBsAg should be excluded.
Patients treated for hepatitis C must have a negative RNA test at
screening and also be HCV RNA negative for at least 3 years prior to
screening in order to be eligible for the trial.
- Suspicion, diagnosis or history of hepatocellular carcinoma (HCC), or
any documented active or suspected malignancy or history of
malignancy with in 5 years prior to screening, except appropriately
treated basal cell carcinoma of the skin or in situ carcinoma of uterine cervix.
- Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2, manifest hypo- or
hyperthyroidism at Visit 1.
- History of chronic or acute pancreatitis or elevation of serum
lipase/amylase > 2x ULN, or fasting serum triglyceride levels of > 500
mg/dL (> 5.65 mmol/L) at screening.
- Known history of HIV (Human Immunodeficiency Virus) infection
and/or tuberculosis and/or an acute COVID-19 infection at Visit 1
(confirmed by SARS CoV-2 RT-PCR test).
- Diagnosis of a serious or unstable disease including hepatic (other than NASH), renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic, psychiatric, immunologic, or hematologic disease and other conditions that, in the clinical judgment of the Investigator, are likely to interfere with the analyses of safety and efficacy in this trial. Patients with a history of organ transplantation except for corneal transplantation and patients with an expected life expectancy of less than 2 years are also excluded.
Further criteria apply. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1) Improvement in liver histological findings |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1) Improvement of liver fat content (yes/ no) defined as at least 30% relative reduction in liver fat content after 48 weeks of treatment compared to baseline assessed by magnetic resonance imaging proton density fat fraction measurement (MRI-PDFF)
2) Absolute and relative change of liver fat content from baseline after 48 weeks of treatment assessed by MRI-PDFF
3) Improvement of fibrosis (yes/ no) defined as at least one stage decrease in fibrosis stage after 48 weeks of treatment assessed by liver biopsy
4) Absolute change from baseline in NAS after 48 weeks of treatment assessed by liver biopsy |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) week 48
2) week 48
3) week 48
4) week 48
|
|
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 65 |
| 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 |
| China |
| Hong Kong |
| Israel |
| Japan |
| Korea, Republic of |
| Malaysia |
| New Zealand |
| Singapore |
| Taiwan |
| United States |
| Austria |
| France |
| Poland |
| Netherlands |
| Spain |
| Czechia |
| Germany |
| Greece |
| Italy |
| Belgium |
| Hungary |
| Portugal |
| United Kingdom |
|
| 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
|
|
| 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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