Fig 1.
Cohorts dosed during the SAD study.
Abbreviations: A = active drug (GSK3494245); Cmax = Maximum Plasma Concentration; COVID-19 = Coronavirus Disease 2019; DEC = dose escalation committee; n = number of participants; P = placebo; SAD = single ascending dose. Notes: In cohort 1 (red), participants received 20 mg (period 1) and 40 mg of GSK3494245 (period 2) or placebo under fasted conditions in a 3:1 ratio (6A:2P). Periods 3 and 4 did not take place due to a site closure associated with the COVID-19 lockdown. In cohort 2 (green), participants received 40, 80, 120, and 160 mg of GSK3494245 (periods 1, 2, 3, and 4, respectively) or placebo under fasted conditions in a 3:1 ratio (6A:2P). In cohort 2A (blue), participants received 150 mg of GSK3494245 or placebo (period 1) under fasted conditions in a 3:1 ratio (6A:2P). Periods 2, 3, and 4 did not take place due to a participant exceeding the Cmax stopping criterion. In cohort 3 (orange), participants received 80 mg of GSK3494245 under fasted conditions, 80 mg of GSK3494245 under fed conditions, placebo under fasted conditions or placebo under fed conditions in a 1:1:1:1 ratio (16A fed: 16A fasted:16P fed:16 P fasted). In cohort 3A (purple), participants received 160 mg (period 1) and 240 mg of GSK3494245 (period 2) or placebo under fed conditions in a 3:1 ratio (6A:2P). A decision was made by the DEC not to proceed with further dose escalation following the 240 mg dose.
Fig 2.
Abbreviations: n = number of participants; P = placebo; PK = pharmacokinetic. Notes: a The “screened population” included all participants who were screened for eligibility (n = 150). Participants who received “no treatment” (n = 23) met the eligibility criteria but did not enter the study. The “enrolled population” included all participants who passed screening and entered the study – this included the “randomized population” (n = 59). b Reasons for screening failure: (i) did not meet inclusion/exclusion criteria (n = 58); (ii) withdrawal by participant (n = 6); (iii) physician decision (n = 4). c In cohort 1, the dosing schedules in periods 1-2 were (i) 20 mg in Period 1-(P in Period 2; (ii) P-40 mg; (iii) 20-40 mg; and (iv) 20-40 mg, respectively. In cohort 2, the dosing schedules in periods 1-4 were: (i) 40-80-120 mg-P; (ii) 40-80 mg-P-160 mg; (iii) 40 mg-P-120-160 mg; and (iv) P-80-120-160 mg, respectively. In cohort 2A, the dosing schedules in period 1 were 150 mg; 150 mg; 150 mg; P. In cohort 3, the dosing schedules in periods 1-4 were: (i) P(fed)-P(fasted)-80 mg (fasted)-80 mg (fed); (ii) P(fasted)-80 mg (fed)-P(fed)-80 mg(fasted); (iii) 80 mg(fed)-80 mg (fasted)-P(fasted)-P(fed); and (iv) 80 mg (fasted)-P(fed)-80 mg(fed)-P(fasted), respectively. In Cohort 3A, the dosing schedules in periods 1-2 were: (i) P-240 mg; (ii) 160 mg-P; (iii) 160-240mg; and (iv) 160-240 mg, respectively.
Table 1.
Summary of participants’ demographic characteristics.
Table 2.
Summary of AEs ranked by overall frequency and system organ class.
Table 3.
Summary GSK3494245 PK parameters after single-dose administration for each cohort.
Fig 3.
Mean plasma concentration-time profile of GSK3494245 after administration of single ascending doses.
Notes: The mean plasma concentration (ng/mL) of GSK3494245 after administration of single ascending doses under fasted or fed conditions is shown relative to the planned time (hours) on linear (left) or semi-logarithmic (right) scales. The horizontal line on the semi-logarithmic scale (right) shows the lower limit of quantification of 10 ng/mL.
Table 4.
Analysis of the dose-proportionality of GSK3494245.
Table 5.
Analysis of the food effect on the PK values of GSK3494245 (cohort 3).