| Outcome Measures: |
The primary endpoint is the improvement (yes/ no) from baseline in liver histological findings based on liver biopsy after 48 weeks of treatment in patients with NASH (NAS greater than or equal to 4, fibrosis F1-F3). NAFLD activity score (NAS) represents the sum of scores for steatosis (0-3), lobular inflammation (0-3) and ballooning (0-2). <br>Improvement in histological findings is defined as a composite of:<br>Improvement in NASH: Decrease of at least 2 points in NAS with at least 1 point decrease in NAS subscore of either lobular inflammation or ballooning<br>AND No worsening of fibrosis, defined as absence of any increase in the fibrosis stage.[Baseline (Visit 1a) and Week 48 post-intervention commencement. ]Improvement of fibrosis (yes/ no) defined as at least one stage decrease in fibrosis stage after 48 weeks of treatment assessed by liver biopsy. Assessment of liver biopsy specimens will be set-up in a blinded fashion. It will be based on the NAFLD scoring system (NAS), developed by the NASH clinical research network (CRN).[Screening (Visit 1a) and Week 48 post-intervention commencement. ];Absolute change from baseline in NAFLD Activity Score (NAS) after 48 weeks of treatment assessed by liver biopsy[Screening (Visit 1a) and Week 48 post-intervention commencement. ];Pharmacokinetic endpoints for BI 456906: Cpre,N (pre-dose concentration of the analyte in plasma immediately before dose N) assessed using serum assay. [Collected prior to administration of the study drug at Week 1, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12, Week 16, Week 20, Week 24, Week 28, Week 36, Week 48 and at Week 52 post-intervention commencement. ];Plasma concentration of BI 456906 will be used for the evaluation of dose-proportionality.[Blood collection prior to administration of study drug at Week 1, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12, Week 16, Week 20, Week 24, Week 28, Week 36, Week 48 and at Week 52 post-intervention commencement. ];Plasma concentration of BI 456906 will be used for the evaluation of attainment of steady state.[Blood collection prior to study drug administration at Week 1, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12, Week 16, Week 20, Week 24, Week 28, Week 36, Week 48 and at Week 52 post-intervention commencement. ];Overall safety as assessed from adverse events (AEs coded using the current version of the Medical Dictionary of Regulatory Activities (MedDRA)), vital signs assessed by clinical examination, safety laboratory parameters assessed by blood collection and cardiac health assessed by 12-lead ECG. [Overall safety will be assessed at various timepoints as outlined below.
<br>Adverse Events: Assessed at every patient visit.
<br>Vitals signs: Screening and Day 1, Day 8, Day 15, Day 22, Week4, Week 6, Week 8, Week 10, Week 12, Week 16, Week 20, Week 24, Week 28, Week 32, Week 36, Week 40, Week 44, Week 48 and Week 52 post-intervention commencement.
<br>Laboratory tests and 12-lead ECG: Screening, Day 1, Day 15, Week 4, Week 6, Week 8, Week 10, Week 12, Week 16, Week 20, Week 24, Week 28, Week 32, Week 36, Week 40, Week 44, Week 48 and Week 52 post-intervention commencement. ];Improvement of liver fat content (yes/ no) defined as at least 30% relative reduction in
<br>liver fat content after 48 weeks of treatment compared to baseline assessed by magnetic
<br>resonance imaging proton density fat fraction measurement (MRI-PDFF)[Baseline (Visit 1), Week 28 and Week 48 post-intervention commencement. ]; Absolute and relative change of liver fat content from baseline after 48 weeks of treatment assessed by MRI-PDFF. This is a composite endpoint.[Screening (Visit 1), Week 28 and Week 48 post-intervention commencement. ]
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