The pharmacokinetic parameter Cmax, the highest concentration of lixivaptan measured in plasma after multiple doses of drug, will be calculated from the observed concentration of lixivaptan and summarized by cohort.

The PKAS consisted of all 31 subjects in the Safety analysis set who received lixivaptan, underwent plasma PK sampling, and were evaluable for this PK outcome. Of these, all 31 subjects contributed to the PK data on Day 1 (am); 30 contributed data to Day 1 (pm); and 29 contributed data to Day 7 (am) and (pm).

The pharmacokinetic parameter Cmax, the highest concentration of WAY-141624 measured in plasma after multiple doses of drug, will be calculated from the observed concentration of WAY-141624 and summarized by cohort.

The PKAS consisted of all 31 subjects in the Safety analysis set who received lixivaptan, underwent plasma PK sampling, and were evaluable for this PK outcome. Missing values and substantial deviations from planned dosing interval durations meant results were excluded from subjects at various time points.

The pharmacokinetic parameter Cmax, the highest concentration of WAY-138451 measured in plasma after multiple doses of drug, will be calculated from the observed concentration of WAY-138451 and summarized by cohort.

The PKAS consisted of all 31 subjects in the Safety analysis set who received lixivaptan, underwent plasma PK sampling, and were evaluable for this PK outcome. Missing values, substantial deviations, and <3 quantifiable postdose WAY-138451 concentrations meant results were excluded from subjects at various time points.

The pharmacokinetic parameter Cmax, the highest concentration of WAY-138758 measured in plasma after multiple doses of drug, will be calculated from the observed concentration of WAY-138758 and summarized by cohort.

The PKAS consisted of all 31 subjects in the Safety analysis set who received lixivaptan, underwent plasma PK sampling, and were evaluable for this PK outcome. Of these, all 31 subjects contributed to the PK data on Day 1 (am); 30 contributed data to Day 1 (pm); and 29 contributed data to Day 7 (am) and (pm). Substantial deviations from planned dosing interval durations meant additional results were excluded from subjects at various time points.

The pharmacokinetic parameter tmax, the time taken to reach the highest concentration of lixivaptan in plasma after multiple doses of drug, will be calculated from the observed concentration of lixivaptan and summarized by cohort.

The PKAS consisted of all 31 subjects in the Safety analysis set who received lixivaptan, underwent plasma PK sampling, and were evaluable for this PK outcome. Of these, all 31 subjects contributed to the PK data on Day 1 (am); 30 contributed data to Day 1 (pm); and 29 contributed data to Day 7 (am) and (pm). Substantial deviations from planned dosing interval durations meant results were excluded from subjects at various time points.

The pharmacokinetic parameter tmax, the time taken to reach the highest concentration of WAY-141624 in plasma after multiple doses of drug, will be calculated from the observed concentration of WAY-141624 and summarized by cohort.

The PKAS consisted of all 31 subjects in the Safety analysis set who received lixivaptan, underwent plasma PK sampling, and were evaluable for this PK outcome. Missing values and substantial deviations from planned dosing interval durations meant results were excluded from subjects at various time points.

The pharmacokinetic parameter tmax, the time taken to reach the highest concentration of WAY-138451 in plasma after multiple doses of drug, will be calculated from the observed concentration of WAY-138451 and summarized by cohort.

The PKAS consisted of all 31 subjects in the Safety analysis set who received lixivaptan, underwent plasma PK sampling, and were evaluable for this PK outcome. Missing values, substantial deviations from planned dosing interval durations, and <3 quantifiable postdose WAY-138451 concentrations meant results were excluded from subjects at various time points.

The pharmacokinetic parameter tmax, the time taken to reach the highest concentration of WAY-138758 in plasma after multiple doses of drug, will be calculated from the observed concentration of WAY-138758 and summarized by cohort.

The PKAS consisted of all 31 subjects in the Safety analysis set who received lixivaptan, underwent plasma PK sampling, and were evaluable for this PK outcome. All 31 subjects in the PKAS contributed to the PK data on Day 1 (am); 30 contributed data to Day 1 (pm); and 29 contributed data to Day 7 (am) and (pm). Substantial deviations from planned dosing interval durations and missing values meant results were excluded from subjects at various time points.

The pharmacokinetic parameter AUC(0-last) for lixivaptan will be calculated using the linear trapezoidal rule for increasing values and the log trapezoidal rule for decreasing values, summarized by cohort.

The PKAS consisted of all 31 subjects in the Safety analysis set who received lixivaptan, underwent plasma PK sampling, and were evaluable for this PK outcome. All 31 subjects in the PKAS contributed to the PK data on Day 1 (am); 30 contributed data to Day 1 (pm); 29 contributed data to Day 7 (am), and 27 contributed data to Day 7 (pm). Substantial deviations from planned dosing interval durations and missing values meant results were excluded from subjects at various time points.

The pharmacokinetic parameter AUC(0-last) for WAY-141624 will be calculated using the linear trapezoidal rule for increasing values and the log trapezoidal rule for decreasing values and summarized by cohort.

The PKAS consisted of all 31 subjects in the Safety analysis set who received lixivaptan, underwent plasma PK sampling, and were evaluable for this PK outcome. Missing values and substantial deviations from planned dosing interval durations meant results were excluded from subjects at various time points.

The pharmacokinetic parameter AUC(0-last) for WAY-138451 will be calculated using the linear trapezoidal rule for increasing values and the log trapezoidal rule for decreasing values and summarized by cohort.

The PKAS consisted of all 31 subjects in the Safety analysis set who received lixivaptan, underwent plasma PK sampling, and were evaluable for this PK outcome. Missing values, substantial deviations from planned dosing interval durations, and <3 quantifiable postdose WAY-138451 concentrations meant results were excluded from subjects at various time points.

The pharmacokinetic parameter AUC(0-last) for WAY-138758 will be calculated using the linear trapezoidal rule for increasing values and the log trapezoidal rule for decreasing values and summarized by cohort.

The PKAS consisted of all 31 subjects in the Safety analysis set who received lixivaptan, underwent plasma PK sampling, and were evaluable for this PK outcome. Missing values and substantial deviations from planned dosing interval durations meant results were excluded from subjects at various time points.

The pharmacokinetic parameter AUC(0-inf) for lixivaptan will be calculated using the linear trapezoidal rule for increasing values, the log trapezoidal rule for decreasing values, and extrapolated to infinity by addition of the last quantifiable observed concentration divided by the elimination rate constant and summarized by cohort.

Upon final PK data analysis, it was evident based upon Day 7 PM profiles (sampled out to 96 hours) that lixivaptan did not appear to have concentration-time data in the terminal phase for Day 1 (AM) or Day 7 AM due to the limited time frame of the dosing intervals of 10 hours. Therefore, the terminal slope-related PK parameter of AUC(0-inf), planned in the protocol/SAP for Day 1 AM, was unable to be calculated due to insufficient sampling duration prior to the PM dose.

The pharmacokinetic parameter AUC(0-inf) for WAY-141624 will be calculated using the linear trapezoidal rule for increasing values, the log trapezoidal rule for decreasing values, and extrapolated to infinity by addition of the last quantifiable observed concentration divided by the elimination rate constant and summarized by cohort.

Upon final PK data analysis, it was evident based upon Day 7 PM profiles (sampled out to 96 hours) that WAY-141624 did not appear to have concentration-time data in the terminal phase for Day 1 (AM) or Day 7 AM due to the limited time frame of the dosing intervals of 10 hours. Therefore, the terminal slope-related PK parameter of AUC(0-inf), planned in the protocol/SAP for Day 1 AM, was unable to be calculated due to insufficient sampling duration prior to the PM dose.

The pharmacokinetic parameter AUC(0-inf) for WAY-138451 will be calculated using the linear trapezoidal rule for increasing values, the log trapezoidal rule for decreasing values, and extrapolated to infinity by addition of the last quantifiable observed concentration divided by the elimination rate constant and summarized by cohort.

Upon final PK data analysis, it was evident based upon Day 7 PM profiles (sampled out to 96 hours) that WAY-138451 did not appear to have concentration-time data in the terminal phase for Day 1 (AM) or Day 7 AM due to the limited time frame of the dosing intervals of 10 hours. Therefore, the terminal slope-related PK parameter of AUC(0-inf), planned in the protocol/SAP for Day 1 AM, was unable to be calculated due to insufficient sampling duration prior to the PM dose.

The pharmacokinetic parameter AUC(0-inf) for WAY-138758 will be calculated using the linear trapezoidal rule for increasing values, the log trapezoidal rule for decreasing values, and extrapolated to infinity by addition of the last quantifiable observed concentration divided by the elimination rate constant and summarized by cohort.

Upon final PK data analysis, it was evident based upon Day 7 PM profiles (sampled out to 96 hours) that WAY-138758 did not appear to have concentration-time data in the terminal phase for Day 1 (AM) or Day 7 AM due to the limited time frame of the dosing intervals of 10 hours. Therefore, the terminal slope-related PK parameter of AUC(0-inf), planned in the protocol/SAP for Day 1 AM, was unable to be calculated due to insufficient sampling duration prior to the PM dose.

The pharmacokinetic parameter t1/2 for lixivaptan, determined as ln2/apparent terminal elimination rate constant, will be calculated and summarized by cohort.

Upon final PK data analysis, it was evident based upon Day 7 (pm) profiles that lixivaptan did not have concentration-time data in the terminal phase for Day 1 (am) due to the limited time frame of the dosing intervals of 10 hours. Therefore, t1/2, planned for Day 1 (am), was unable to be calculated due to insufficient sampling duration prior to the PM dose. Missing values and substantial deviations meant results were excluded from subjects at various time points.

The pharmacokinetic parameter t1/2 for WAY-141624, determined as ln2/apparent terminal elimination rate constant, will be calculated and summarized by cohort.

Upon final PK data analysis, it was evident based upon Day 7 (pm) profiles that WAY-141624 did not have concentration-time data in the terminal phase for Day 1 (am) due to the limited time frame of the dosing intervals of 10 hours. Therefore, t1/2, planned for Day 1 AM, was unable to be calculated due to insufficient sampling duration prior to the PM dose. Missing values and substantial deviations meant results were excluded from subjects at various time points.

The pharmacokinetic parameter t1/2 for WAY-138451, determined as ln2/apparent terminal elimination rate constant, will be calculated and summarized by cohort.

It was evident WAY-138451 did not have concentration-time data in the terminal phase for D1(am) due to the limited time frame of the 10-hour dosing intervals. t1/2, planned for Day 1 AM, was unable to be calculated due to insufficient sampling duration prior to the PM dose. Missing values, substantial deviations and <3 quantifiable postdose WAY-138451 concentrations meant some results were excluded; also, t1/2 could not be calculated for the 2 participants in the low dose lixivaptan/CKD3 cohort.

The pharmacokinetic parameter t1/2 for WAY-138758, determined as ln2/apparent terminal elimination rate constant, will be calculated and summarized by cohort.

Upon final PK data analysis, it was evident based upon Day 7 (pm) profiles that WAY-138758 did not appear to have concentration-time data in the terminal phase for Day 1 (am) due to the limited time frame of the dosing intervals of 10 hours. Therefore, t1/2, planned for Day 1 (am), was unable to be calculated due to insufficient sampling duration prior to the PM dose. Missing values and substantial deviations meant additional results were excluded from subjects at various time points.

The pharmacokinetic parameter λZ for lixivaptan will be determined by linear regression of the terminal points of the log-linear concentration-time curve. The Best Fit method utilized by WinNonlin will be used to identify the terminal linear phase of the concentration-time profile, with visual assessment and adjustment of the selected data points by the PK scientist if warranted. A minimum of 3 data points will be used for determination. Results will be summarized by cohort.

Upon final PK data analysis, it was evident based upon Day 7 (pm) profiles that lixivaptan did not appear to have concentration-time data in the terminal phase for Day 1 (am) due to the limited time frame of the dosing intervals of 10 hours. Therefore, λZ, planned for Day 1 (am), was unable to be calculated due to insufficient sampling duration prior to the PM dose. Missing values and substantial deviations meant additional results were excluded from subjects at various time points.

The pharmacokinetic parameter λZ for WAY-141624 will be determined by linear regression of the terminal points of the log-linear concentration-time curve. The Best Fit method utilized by WinNonlin will be used to identify the terminal linear phase of the concentration-time profile, with visual assessment and adjustment of the selected data points by the PK scientist if warranted. A minimum of 3 data points will be used for determination. Results will be summarized by cohort.

Upon final PK data analysis, it was evident based upon Day 7 (pm) profiles that WAY-141624 did not appear to have concentration-time data in the terminal phase for Day 1 (am) due to the limited time frame of the dosing intervals of 10 hours. Therefore, λZ, planned for Day 1 (am), was unable to be calculated due to insufficient sampling duration prior to the PM dose. Missing values and substantial deviations meant additional results were excluded from subjects at various time points.

The pharmacokinetic parameter λZ for WAY-138451 will be determined by linear regression of the terminal points of the log-linear concentration-time curve. The Best Fit method utilized by WinNonlin will be used to identify the terminal linear phase of the concentration-time profile, with visual assessment and adjustment of the selected data points by the PK scientist if warranted. A minimum of 3 data points will be used for determination. Results will be summarized by cohort.

It was evident WAY-138451 did not appear to have concentration-time data in the terminal phase for D1(am) due to the limited time frame of the dosing intervals of 10 hours. λZ, planned for D1(am), was unable to be calculated due to insufficient sampling duration prior to the pm dose. Missing values, deviations, and <3 quantifiable postdose WAY-138451 concentrations meant results were excluded; also, λZ could not be calculated for the 2 participants in the low dose lixivaptan/CKD3 cohort.

The pharmacokinetic parameter λZ for WAY-138758 will be determined by linear regression of the terminal points of the log-linear concentration-time curve. The Best Fit method utilized by WinNonlin will be used to identify the terminal linear phase of the concentration-time profile, with visual assessment and adjustment of the selected data points by the PK scientist if warranted. A minimum of 3 data points will be used for determination. Results will be summarized by cohort.

Upon final PK data analysis, it was evident based upon Day 7 (pm) profiles that WAY-138758 did not appear to have concentration-time data in the terminal phase for Day 1 (am) due to the limited time frame of the dosing intervals of 10 hours. Therefore, λZ, planned for Day 1 (am), was unable to be calculated due to insufficient sampling duration prior to the pm dose. Missing values and substantial deviations meant additional results were excluded from subjects at various time points.

The pharmacokinetic parameter CL/F for lixivaptan, calculated as: Day 1 AM: dose divided by AUC(0-inf), or Day 7 AM: dose divided by AUC(0-last), will be summarized by cohort.

Upon final PK data analysis, it was evident based upon Day 7 (pm) profiles that lixivaptan did not appear to have concentration-time data in the terminal phase for Day 1 (am) due to the limited time frame of the dosing intervals of 10 hours. Therefore, CL/F, planned for Day 1 (am), was unable to be calculated due to insufficient sampling duration prior to the pm dose. Missing values and substantial deviations meant additional results were excluded from subjects at various time points.

The pharmacokinetic parameter VZ/F for lixivaptan, calculated as CL/F divided by λZ, will be summarized by cohort.

Upon final data analysis, it was evident based upon Day (D) 7(pm) profiles that lixivaptan did not have concentration-time data in the terminal phase for D1(am) due to the limited time frame of the 10-hour dosing intervals. Therefore, VZ/F, planned for D1(am), was unable to be calculated due to insufficient sampling duration prior to the pm dose, and values for the D7(am) time point were not presented. Instead, VZ/F24H was determined and presented as an Other Pre-specified Outcome Measure.

The pharmacokinetic parameter RCmax for lixivaptan, calculated as [Cmax on Day 7]/[Cmax on Day 1], will be summarized by cohort.

Of the 31 subjects in the PKAS, 29 contributed data to Day 7 (am).

The pharmacokinetic parameter RAUC(0-last) for lixivaptan, calculated as [AUC(0-last) on Day 7]/[AUC(0-last) on Day 1], will be summarized by cohort.

Of the 31 subjects in the PKAS, 29 contributed data to Day 7 (am).

The pharmacokinetic parameter AUC(0-14) for lixivaptan will be calculated using the linear trapezoidal rule for increasing values and the log trapezoidal rule for decreasing values. The actual elapsed time for the nominal 14-hour sample will be used for the calculation. Results will be summarized by cohort.

Of the 31 subjects in the PKAS, 29 contributed data to Day 7 (pm).

The pharmacokinetic parameter AUC(0-14) for WAY-141624 will be calculated using the linear trapezoidal rule for increasing values and the log trapezoidal rule for decreasing values. The actual elapsed time for the nominal 14-hour sample will be used for the calculation. Results will be summarized by cohort.

Of the 31 subjects in the PKAS, 29 contributed data to Day 7 (pm).

The pharmacokinetic parameter AUC(0-14) for WAY-138451 will be calculated using the linear trapezoidal rule for increasing values and the log trapezoidal rule for decreasing values. The actual elapsed time for the nominal 14-hour sample will be used for the calculation. Results will be summarized by cohort.

Of the 31 subjects in the PKAS, 29 contributed data to Day 7 (pm).

The pharmacokinetic parameter AUC(0-14) for WAY-138758 will be calculated using the linear trapezoidal rule for increasing values and the log trapezoidal rule for decreasing values. The actual elapsed time for the nominal 14-hour sample will be used for the calculation. Results will be summarized by cohort.

Of the 31 subjects in the PKAS, 29 contributed data to Day 7 (pm).

The pharmacokinetic parameter MRCmax for WAY-141624 will be calculated and corrected for molecular weight of WAY-141624 and parent lixivaptan as: (Cmax,m/Cmax,p)(MWp/MWm), where Cmax,m and MWm are Cmax and molecular weight of WAY-141624, respectively, and Cmax,p and MWp are Cmax and molecular weight of parent lixivaptan, respectively. The following molecular weights are to be used in all MRCmax calculations:

• lixivaptan: 473.93 g/mol
• WAY-141624: 505.95 g/mol

Results will be summarized by cohort.

Of the 31 subjects in the PKAS, 29 contributed data to Day 7 (pm).

The pharmacokinetic parameter MRCmax for WAY-138451 will be calculated and corrected for molecular weight of WAY-138451 and parent lixivaptan as: (Cmax,m/Cmax,p)(MWp/MWm), where Cmax,m and MWm are Cmax and molecular weight of WAY-138451, respectively, and Cmax,p and MWp are Cmax and molecular weight of parent lixivaptan, respectively. The following molecular weights are to be used in all MRCmax calculations:

• lixivaptan: 473.93 g/mol
• WAY-138451: 488.92 g/mol

Results will be summarized by cohort.

Of the 31 subjects in the PKAS, 29 contributed data to Day 7 (pm).

The pharmacokinetic parameter MRCmax for WAY-138758 will be calculated and corrected for molecular weight of WAY-138758 and parent lixivaptan as: (Cmax,m/Cmax,p)(MWp/MWm), where Cmax,m and MWm are Cmax and molecular weight of WAY-138758, respectively, and Cmax,p and MWp are Cmax and molecular weight of parent lixivaptan, respectively. The following molecular weights are to be used in all MRCmax calculations:

• lixivaptan: 473.93 g/mol
• WAY-138758: 426.82 g/mol

Results will be summarized by cohort.

Of the 31 subjects in the PKAS, 29 contributed data to Day 7 (pm).

The pharmacokinetic parameter MRAUC(0-14) for WAY-141624 will be calculated and corrected for molecular weight of WAY-141624 and parent lixivaptan as: (AUC(0-14),m/AUC(0-14),p)(MWp/MWm), where AUC(0-14),m and MWm are AUC(0-14) and molecular weight of WAY-141624, respectively, and AUC(0-14),p and MWp are AUC(0-14) and molecular weight of parent lixivaptan, respectively. The following molecular weights are to be used in all MRAUC(0-14) calculations:

• lixivaptan: 473.93 g/mol
• WAY-141624: 505.95 g/mol

Results will be summarized by cohort.

Of the 31 subjects in the PKAS, 29 contributed data to Day 7 (pm).

The pharmacokinetic parameter MRAUC(0-14) for WAY-138451 will be calculated and corrected for molecular weight of WAY-138451 and parent lixivaptan as: (AUC(0-14),m/AUC(0-14),p)(MWp/MWm), where AUC(0-14),m and MWm are AUC(0-14) and molecular weight of WAY-138451, respectively, and AUC(0-14),p and MWp are AUC(0-14) and molecular weight of parent lixivaptan, respectively. The following molecular weights are to be used in all MRAUC(0-14) calculations:

• lixivaptan: 473.93 g/mol
• WAY-138451: 488.92 g/mol

Results will be summarized by cohort.

Of the 31 subjects in the PKAS, 29 contributed data to Day 7 (pm).

The pharmacokinetic parameter MRAUC(0-14) for WAY-138758 will be calculated and corrected for molecular weight of WAY-138758 and parent lixivaptan as: (AUC(0-14),m/AUC(0-14),p)(MWp/MWm), where AUC(0-14),m and MWm are AUC(0-14) and molecular weight of WAY-138758, respectively, and AUC(0-14),p and MWp are AUC(0-14) and molecular weight of parent lixivaptan, respectively. The following molecular weights are to be used in all MRAUC(0-14) calculations:

• lixivaptan: 473.93 g/mol
• WAY-138758: 426.82 g/mol

Results will be summarized by cohort.

Of the 31 subjects in the PKAS, 29 contributed data to Day 7 (pm).

The number of study participants who experience treatment-emergent adverse events during the study will be counted and summarized by dose level.

Results are presented based on the Safety Analysis Set, which included all subjects who received at least 1 dose of study medication, and were analyzed according to treatment received. The Safety Analysis Set included all 31 subjects who were enrolled in the study.

The number of study participants who experience clinically significant physical examination findings during the study will be counted and summarized by cohort.

Results are presented based on the Safety Analysis Set, which included all subjects who received at least 1 dose of study medication, and were analyzed according to treatment received. The Safety Analysis Set included all 31 subjects who were enrolled in the study.

The number of study participants who experience vital signs (systolic blood pressure, diastolic blood pressure, pulse rate, respiratory rate, and body temperature) meeting the predefined markedly abnormal criteria during the study will be counted and summarized by cohort.

Results are presented based on the Safety Analysis Set, which included all subjects who received at least 1 dose of study medication, and were analyzed according to treatment received. The Safety Analysis Set included all 31 subjects who were enrolled in the study.

The number of study participants who experience 12-lead electrocardiograms meeting the predefined markedly abnormal criteria during the study will be counted and summarized by cohort.

Results are presented based on the Safety Analysis Set, which included all subjects who received at least 1 dose of study medication, and were analyzed according to treatment received. The Safety Analysis Set included all 31 subjects who were enrolled in the study.

The number of study participants who experience clinically meaningful laboratory findings, relating to clinical chemistry, hematology, and urinalysis, during the study will be counted and summarized by cohort.

Results are presented based on the Safety Analysis Set, which included all subjects who received at least 1 dose of study medication, and were analyzed according to treatment received. The Safety Analysis Set included all 31 subjects who were enrolled in the study.

The number of study participants who answered "yes" to the following questions at Day 7 will be counted and summarized by dose level:

• Could you tolerate taking this dose of study drug for the next 12 months?
• Did the study drug make you feel thirsty more often than usual?
• Did the study drug make you go to the bathroom (urinate) more often than usual during the night?
• Would you be comfortable recommending the study drug to another patient with your kidney condition?

Results are presented based on the Safety Analysis Set, which included all subjects who received at least 1 dose of study medication, and were analyzed according to treatment received. The Safety Analysis Set included all 31 subjects who were enrolled in the study.

The number of study participants who answered "not at all" and "slightly" to the following question at Day 7 will be measured:

• If the study drug made you feel thirsty more often than usual, were you bothered by it?

Results are presented based on the Safety Analysis Set, which included all subjects who received at least 1 dose of study medication, and were analyzed according to treatment received. The Safety Analysis Set included all 31 subjects who were enrolled in the study. Answers were not received from all participants.

Changes from baseline in spot urine measurements for samples taken at 0, 1, 2, 4, 6, 9, 10, 11, 12, 14, and 24 hours after the Day 1 and Day 7 doses will be summarized by cohort. The baseline value for each time point after first administration of study drug is the value observed at the corresponding time point on Day -1 (or Day 1 for the AM predose assessment only).

The Pharmacodynamic Analysis Set (PDAS) consisted of all 31 subjects in the Safety analysis set who received lixivaptan. Overall, all 31 subjects contributed PD endpoints to the Day 1/2 assessment; 30 subjects contributed data to the Day 7/8 PD endpoints and scheduled EOS assessments; however, values were not available for all participants at each time point.

Changes from baseline in 24-hour urine output for samples taken on Day 1 and Day 7 will be summarized by cohort. The baseline value was the last value observed prior to first administration of study drug on Day -1.

The PDAS consisted of all 31 subjects in the Safety analysis set who received lixivaptan. Values were not available for all participants in the PDAS at each time point.

Changes from baseline of eGFR derived from the serum creatinine concentrations for samples taken at Day 1 (postdose), Day 2, Day 7, Day 8, and Day 35 will summarized by cohort

The PDAS consisted of all 31 subjects in the Safety analysis set who received lixivaptan. Of these, all 31 subjects contributed PD endpoints to the Day 1/2 assessment; 30 subjects contributed data to the Day 7/8 PD endpoints and scheduled EOS assessments.

Changes from baseline (Day -1) in total kidney volume, measured by abdominal MRI on Day 7 and Day 35, will be summarized by cohort.

The PDAS consisted of all 31 subjects in the Safety analysis set who received lixivaptan. Overall, all 31 subjects contributed PD endpoints to the Day 1/2 assessment; 30 subjects contributed data to the Day 7/8 PD endpoints and scheduled EOS assessments; however, values were not available for all participants at each time point.

Changes from baseline (Day -1) in liver volume, measured by abdominal MRI on Day 7 and Day 35, will be summarized by cohort.

The PDAS consisted of all 31 subjects in the Safety analysis set who received lixivaptan. Values were not available for all participants in the PDAS at each time point.

Changes from baseline (Day -1) in plasma copeptin, a marker for circulating vasopressin, at Day 2, Day 7, and Day 35 will be summarized by cohort.

The PDAS consisted of all 31 subjects in the Safety analysis set who received lixivaptan. Of these, all 31 subjects contributed PD endpoints to the Day 1/2 assessment; 30 subjects contributed data to the Day 7/8 PD endpoints and scheduled EOS assessments.

Changes from baseline in serum creatinine for samples taken at Day 2, Day 7, Day 8, and Day 35 will be summarized by cohort.

Results are presented based on the Safety Analysis Set, which included all subjects who received at least 1 dose of study medication, and were analyzed according to treatment received. The Safety Analysis Set included all 31 subjects who were enrolled in the study.

Changes from baseline in BUN for samples taken at Day 2, Day 7, Day 8, and Day 35 will be summarized by cohort.

Results are presented based on the Safety Analysis Set, which included all subjects who received at least 1 dose of study medication, and were analyzed according to treatment received. The Safety Analysis Set included all 31 subjects who were enrolled in the study.

The pharmacokinetic parameter VZ/F24H for lixivaptan, calculated as CL/F24H divided by Day 7 PM λZ, will be summarized by cohort. VZ/F24H was not specified in the statistical analysis plan and was calculated for the combined 24-hour period including AM and PM dosing intervals on Day 7. This parameter replaces VZ/F initially planned for the Day 7 AM dose.

Of the 31 subjects in the PKAS, 29 contributed data to Day 7 (am). Data were excluded for 1 subject in the low dose/CKD1 or 2 cohort from Day 1 (pm) onwards due to substantial deviations from planned dosing interval durations. Missing values and substantial deviations meant additional results were excluded from subjects at various time points.

The number of study participants who answered "not at all" and "slightly" to the following question at Day 7 will be measured:

• If the study drug made you go to the bathroom (urinate) more often than usual during the night, did it bother you?

Results are presented based on the Safety Analysis Set, which included all subjects who received at least 1 dose of study medication, and were analyzed according to treatment received. The Safety Analysis Set included all 31 subjects who were enrolled in the study. Answers were not received from all participants.