Procedures and assessments
hepatocellular ballooning, itch, fibrosis, sleep loss, NASH, lobular inflammation, steatosis, dyslipidemia
LIVER FIBROSIS, FIBROSIS, BLOOD, STEATOSIS, DYSLIPIDEMIA
Safety assessments included monitoring of AEs and SAEs, with their severity and relationship to study drug. The Medical Dictionary for Regulatory Activities (MedDRA) v.23.0 was used for the reporting of AEs.Serum samples for the quantification of target engagement markers FGF19 and C4 were collected predose at baseline and at week 12 in Parts A and B, and predose at baseline and at weeks 12, 24, 40 and 48 in Part C. Samples were collected predose and 4 h postdose at week 6 in all parts.Blood samples for the assessment of liver enzymes (ALT, AST, GGT, ALP) were obtained at screening, baseline and weeks 1, 2, 4, 6, 8, 12 and 16 in all parts; and additionally at weeks 20, 24, 32, 40, 48 and 52 in Part C. Hy’s law criteria (total bilirubin levels >2× upper limit of normal and ALT >3× upper limit of normal)Fibroscan was an optional assessment; if sites had equipment available, it was performed at baseline and at week 12 in all parts and at weeks 12, 24 and 48 in Part C. Assessments at end-of-treatment were not performed in the case of premature treatment discontinuation unless the participant had received ≥8 weeks of therapy. Enhanced liver fibrosis panel and fibrosis biomarker tests were performed at screening, baseline and week 12 in all parts, and additionally at weeks 24 and 48 in Part C.Fasting lipids were measured at screening, baseline and weeks 2, 6, 12 and 16 in Parts A and B; and at screening, baseline and weeks 2, 6, 12, 20, 24, 40, 48 and 52 in Part C. Management of treatment-emergent dyslipidemia was not prespecified in the study protocol.Blood collection for PK was performed at week 1 (predose and 2 h postdose) and weeks 2, 4, 6, 8 and 12 (predose) in Part A; and at week 2 (predose and 2 h postdose), week 6 (predose and 4 h postdose), and weeks 4, 8 and 12 (postdose) in Part B. In Part C, blood collection for PK was performed for predose and postdose as the last activity of the visit at weeks 12, 24 and 48, and postdose as the last activity of the visit at weeks 6 and 40.Itch severity and impact of nocturnal itch on sleep were determined on a 10-cm VAS (score range: 0 (no itch at all/no sleep loss) to 10 (the worst imaginable itch/cannot sleep at all)). Assessments were performed at screening (for sleep only), baseline and weeks 6, 12 and 16 in Parts A and B; and at screening (for sleep only), baseline and weeks 2, 6, 12, 24, 48 and 52 in Part C.Liver MRI scans were acquired at screening and at week 12 in Parts A and B, and at baseline and weeks 12, 24 and 48 in Part C. Week 12 assessment was not done if the participant prematurely discontinued treatment before week 8. All MRI scans were performed locally (on GE, Philips and Siemens at 1.5 T and 3 T; and Hitachi at 1.5 T, whichever was available) and were evaluated by the central MRI laboratory (BioTelemetry Research, Rochester, NY, USA), blinded to the investigator, participant and sponsor until after the completion of study or study part and database lock.In Part C, liver biopsies were obtained for all patients at baseline and week 48. Biopsies were stained using hematoxylin and eosin and Masson trichrome stains. Biopsy sections were evaluated by the central histopathologist to confirm eligibility before randomization. Paired review of biopsies was performed after all patients’ participation was completed; baseline and week 48 biopsies of each patient were read together, at the same time, by the central histopathologist, blinded to participant identification, treatment and temporal sequence of samples (baseline or week 48). NASH features in the biopsies were graded using the semiquantitative NASH CRN Histologic Scoring System. This scoring system is composed of the NAS to evaluate the key features of NASH (steatosis, lobular inflammation and hepatocellular ballooning), and the fibrosis score to evaluate fibrosis stageIn addition to the central pathologist’s assessment, unstained sections of 198 paired liver biopsies (baseline and week 48) from 99 patients (fibrosis stage 2 (