Safety
orthostatic dysregulation, cirrhosis
ADVERSE EVENTS, SECONDARY, CIRRHOSIS, ADVERSE EVENT
Investigator-defined, drug-related AEs (primary end point) were reported for 2 patients with CP-A cirrhosis (8.3%: n = 1, 3 mg BID; n = 1, placebo) and 5 patients with CP-B cirrhosis (20.0%: n = 3, 2 mg BID; n = 2, 3 mg BID) (Table Summary of treatment-emergent adverse events according to cirrhosis Child–Pugh class and BI 685509 doseAbbreviations: AE, adverse event; BID, twice daily; CP, Child–Pugh; TEAE, treatment-emergent adverse event.TEAEs were reported for 3 patients with CP-A cirrhosis (12.5%) and 8 patients with CP-B cirrhosis (32.0%); no HVs reported TEAEs (Table No relevant changes from baseline in systolic BP, diastolic BP, HR, bodyweight (secondary end points), MAP, hip circumference, or waist circumference were seen in patients with CP-A or CP-B cirrhosis at day 28 or in HVs (Table Change from baseline in secondary safety end points at day 28n=5.n=6.Abbreviations: BID, twice daily; CP, Child–Pugh.Overall, 5 patients were reported with orthostatic dysregulation (n = 1, CP-A 3 mg BID; n = 2 each per CP-B 2 mg BID and 3 mg BID); no matched HVs were reported with orthostatic dysregulation. For CP-A 1 mg BID and CP-B 2 mg BID patients, systolic BP after standing up tended to decrease for all 1 hour postdose measurements compared with predose measurements, and pulse rate tended to increase 1 hour postdose compared with predose measurements (Supplemental Figure S2, Two patients with CP-A cirrhosis progressed to CP-B during treatment (n = 1 each per 1 mg BID and 3 mg BID), with the patient in the 3 mg BID dose group returning to CP-A at follow-up. Two patients with CP-B cirrhosis were reported with a temporary shift to CP-A (n = 1 each per 1 mg BID and placebo), and 1 patient reported a temporary shift to CP-C (1 mg BID) due to decreased serum albumin. All patients reporting a shift in CP classification continued treatment.During treatment, 7 patients with CP-A cirrhosis and 12 patients with CP-B cirrhosis (no HVs) had slightly raised direct bilirubin levels (maximum values: 0.43–0.76 mg/dL and 0.44–1.24 mg/dL, respectively). Of these, only 2 episodes were considered possibly clinically significant (both in patients with CP-B cirrhosis; maximum values: 1.14 mg/dL and 1.24 mg/dL). Furthermore, during treatment, 12 patients with CP-A cirrhosis, 11 patients with CP-B cirrhosis, and 1 HV had slightly raised alkaline phosphatase levels (maximum values: 119–214 U/L, 118–203 U/L, and 151 U/L, respectively); none of these episodes were considered clinically significant.