Subjects
SAD
A total of 109 healthy male participants took part in the study. The SAD substudy comprised 56 randomized participants: 42 participants across the single dose KCL‐286 treatment arms and 14 participants in the placebo arm. Across the cohorts, participants randomized to KCL‐286 included 3 to 1 mg, 4 to 2 mg, 5 to 48 mg and 6 participants each to 4, 8, 12, 24 and 100 mg. The 2‐mg cohort planned to include 3 participants treated with KCL‐286; however, 1 participant randomized to 2 mg KCL‐286 withdrew consent and was replaced. The 48‐mg cohort included 1 fewer participant randomized to KCL‐286 than planned (as agreed by the safety review committee). Therefore, 55 participants completed the SAD substudy.Part A: FI (single dose crossover with 7‐day washout). For the FI substudy, a dose of 6 mg KCL‐286 was selected based on the data from the SAD. The dose was chosen to ensure exposure did not exceed previous safe doses assuming a 2‐fold increase in bioavailability following food. The FI cohort comprised 8 randomized participants as planned, 4 to the fasted–fed crossover arm and 4 to fed–fasted crossover arm. One participant from each FI arm discontinued the study: 1 in the 6‐mg fasted–fed arm discontinued due to an AE and use of prohibited medication and 1 in the 6‐mg fed–fasted arm discontinued due to noncompliance and was lost to follow‐up. The remaining 6 participants in the FI cohort (3 participants in each arm) completed the study as planned.Part B: MAD (6 or 7 days of dosing once per day, fasted condition). This part of the study comprised 40 randomized participants: 30 across the multiple dose KCL‐286 treatment arms and 10 in the placebo arm. Across the cohorts, participants randomized to KCL‐286 included 6 each to the 6, 12, 24, 72 and 100‐mg multiple dose treatment arms. All 40 participants completed the MAD substudy as planned. The Surrey Clinical Research Centre had to close in December 2019; at this time, 6 SAD cohorts and the FI cohort were completed. Partially completed were SAD Cohort S7 (7 out of 8 participants dosed) and MAD Cohort M1 (5 out of 8 participants dosed). The trial was continued at Richmond Pharmacology, once covid restrictions allowed. The decision was taken to repeat MAD Cohort M1 in full (8 participants) to ensure that the full cohort was from the same study site. Furthermore, to reduce the potential for site bias in the analyses, 5 participants from the Surrey site randomized to Cohort M1 (4 randomized to active treatment and 1 randomized to placebo) were removed from the safety population.The demographics of the participants are summarized in Table Summary of participant demographics.Abbreviations: FI, food interaction; MAD, multiple ascending dose; SAD, single ascending dose; SD, standard deviation.