Exposure to Study Medication
In all randomized participants, exposure of ≥361 days was achieved in 33 of 48 participants (69%) in the tolvaptan arm and 29 of 43 participants (67%) in the placebo arm. The average daily dose was 41 (SD 17) mg in the tolvaptan arm and 51 (SD 14) mg in the placebo arm. The most frequent modal total daily doses at month 12 were 45 mg for tolvaptan (39% participants) and 60 mg for placebo (53% participants) in group 1 and 15 mg and 22.5 mg (31% participants each) for tolvaptan and 45 mg (67% participants) for placebo in group 2 (Treatment adherence in all participants, as determined by returned study medication, was ≥90% for 46 of 48 participants (96%) in the tolvaptan arm and 40 of 43 participants (93%) in the placebo group. Plasma concentrations of the tolvaptan oxobutyric acid metabolite (DM-4103) were used to verify adherence in tolvaptan-treated participants. DM-4103 concentrations at week 1 and month 1 were consistent with reported dosing for all participants with an evaluable sample. At month 6, one of 42 participants (2%) with a pharmacokinetic sample was not adherent with reported dosing, and at month 12, five additional participants (for a total of six of 40 participants [15%]) had DM-4103 concentrations indicating limited to no dosing within the previous weeks. Of these six nonadherent participants, five participants were from group 1 and one participant was from group 2.