Multiple ascending dose study.

The MAD study was a phase 1, single-center, randomized, double-blind, placebo-controlled, prospective, parallel design study conducted in 30 healthy male and female subjects. The dose levels in this study were not to exceed the dose levels which were well tolerated in the SAD/FE study. The increase from one dose level to the next one was not to be more than 3-fold. As an additional safety measure for a multiple-dose study, further eligibility criteria were required to be met such as bilirubin, aminotransferase, and alkaline phosphatase levels within the normal range; additional exclusion criteria were history of myasthenia gravis, hepatitis, and/or jaundice associated with the use of any antibacterial treatment, congenital prolongation of the QTc interval, and any ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia or clinically significant bradycardia.

The study was conducted in 3 cohorts, with 10 subjects per cohort receiving nafithromycin or matching placebo for 7 consecutive days. Details of the study cohorts are presented in Table 2. On the basis of the safety, tolerability, and PK results of the SAD/FE study, the once-daily 600-mg dose was selected as the first dose to be evaluated in the MAD study. Ultimately, three cohorts were administered ascending multiple oral doses of from 600 mg to 1,000 mg nafithromycin or matching placebo once daily. Dosing was conducted under fed conditions on each dosing day. Doses were escalated only if the safety and tolerability of the previous dose level were acceptable to the investigator and after a statement of no objection of the ethics committee.

Subjects were screened within 3 weeks prior to check-in to the study center. Subjects stayed in the center for 11 days (10 nights) and left the center after completion of the assessments scheduled for 72 h after the last drug administration. In each cohort, a follow-up medical examination was performed between 7 and 14 days after the last assessment and consisted of physical examination and vital signs, ECG, and clinical laboratory tests.