Trial Outcomes & Findings for Study of Efficacy & Safety for 3 Infusion Regimens of IV Conivaptan in Subjects With Euvolemic or Hypervolemic Hyponatremia (NCT NCT00478192)

Last Updated: 2014-05-15

Results Overview

Baseline is the average of the two most recent serum sodium levels prior to start of dosing on day 1. Hour 48: Hour 48 or time that ended study participation prior to the hour 48 assessment. Change is calculated as Hour 48 - Baseline.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

50 participants

Primary outcome timeframe

Baseline and 48 hours

Results posted on

2014-05-15

Participant Flow

One patient in the Placebo arm discontinued prior to dosing and therefore was not included in the Full Analysis Set (FAS) or the Safety Analysis Set (SAF).

Participant milestones

Participant milestones
Measure	Regimen 1 Conivaptan QD 20 mg conivaptan once a day	Regimen 2 Conivaptan BID 20 mg conivaptan two times a day	Regimen 3 Placebo
Overall Study STARTED	20	20	10
Overall Study Full Analysis Set / Safety Analysis Set	20	20	9
Overall Study End of Treatment	18	16	8
Overall Study COMPLETED	16	15	8
Overall Study NOT COMPLETED	4	5	2

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Study of Efficacy & Safety for 3 Infusion Regimens of IV Conivaptan in Subjects With Euvolemic or Hypervolemic Hyponatremia

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Regimen 1 Conivaptan QD n=20 Participants 20 mg conivaptan once a day	Regimen 2 Conivaptan BID n=20 Participants 20 mg conivaptan two times a day	Regimen 3 Placebo n=9 Participants	Total n=49 Participants Total of all reporting groups
Age, Continuous	58.6 years STANDARD_DEVIATION 17.36 • n=5 Participants	67.5 years STANDARD_DEVIATION 14.70 • n=7 Participants	61.8 years STANDARD_DEVIATION 20.19 • n=5 Participants	62.8 years STANDARD_DEVIATION 17.01 • n=4 Participants
Sex: Female, Male Female	7 Participants n=5 Participants	11 Participants n=7 Participants	8 Participants n=5 Participants	26 Participants n=4 Participants
Sex: Female, Male Male	13 Participants n=5 Participants	9 Participants n=7 Participants	1 Participants n=5 Participants	23 Participants n=4 Participants
Race/Ethnicity, Customized Asian	7 participants n=5 Participants	4 participants n=7 Participants	3 participants n=5 Participants	14 participants n=4 Participants
Race/Ethnicity, Customized Black or African American	1 participants n=5 Participants	1 participants n=7 Participants	2 participants n=5 Participants	4 participants n=4 Participants
Race/Ethnicity, Customized White	12 participants n=5 Participants	15 participants n=7 Participants	4 participants n=5 Participants	31 participants n=4 Participants

PRIMARY outcome

Timeframe: Baseline and 48 hours

Population: Full Analysis Set (FAS): all randomized patients who received at least one dose of study drug and who had baseline serum sodium data. The number of participants analyzed per arm represents FAS. The numbers of participants for each visit are noted in the category titles.

Outcome measures

Outcome measures
Measure	Regimen 1 Conivaptan QD n=20 Participants 20 mg conivaptan once a day	Regimen 2 Conivaptan BID n=20 Participants 20 mg conivaptan two times a day	Regimen 3 Placebo n=9 Participants
Change in Serum Sodium From Baseline to the 48 Hour Assessment or Study Drug Discontinuation. Baseline (N= 20; 20; 9)	126.03 mEq/L Standard Deviation 4.017	126.39 mEq/L Standard Deviation 3.581	125.55 mEq/L Standard Deviation 3.648
Change in Serum Sodium From Baseline to the 48 Hour Assessment or Study Drug Discontinuation. Hour 48 (N=19; 17; 8)	130.4 mEq/L Standard Deviation 5.21	133.4 mEq/L Standard Deviation 4.82	127.6 mEq/L Standard Deviation 2.36
Change in Serum Sodium From Baseline to the 48 Hour Assessment or Study Drug Discontinuation. Change from Baseline (N=19; 17; 8)	4.00 mEq/L Standard Deviation 3.80	7.36 mEq/L Standard Deviation 4.04	1.16 mEq/L Standard Deviation 2.86

SECONDARY outcome

Timeframe: Baseline, Hour 4, Hour 12, Hour 16, Hour 24, Hour 28, Hour 36, Hour 40 and Hour 48

Outcome measures

Outcome measures
Measure	Regimen 1 Conivaptan QD n=20 Participants 20 mg conivaptan once a day	Regimen 2 Conivaptan BID n=20 Participants 20 mg conivaptan two times a day	Regimen 3 Placebo n=9 Participants
Change From Baseline in Serum Sodium Level at Each Time Point Through the 48 Hour Assessment Baseline (N=20; 20; 9)	126.03 mEq/L Standard Deviation 4.02	126.39 mEq/L Standard Deviation 3.58	125.55 mEq/L Standard Deviation 3.65
Change From Baseline in Serum Sodium Level at Each Time Point Through the 48 Hour Assessment Hour 4 (N=19; 20; 8)	128.03 mEq/L Standard Deviation 4.62	128.47 mEq/L Standard Deviation 4.21	125.80 mEq/L Standard Deviation 4.63
Change From Baseline in Serum Sodium Level at Each Time Point Through the 48 Hour Assessment Change at Hour 4 (N=19; 20; 8)	1.59 mEq/L Standard Deviation 2.32	2.08 mEq/L Standard Deviation 2.65	-0.63 mEq/L Standard Deviation 2.77
Change From Baseline in Serum Sodium Level at Each Time Point Through the 48 Hour Assessment Hour 12 (N=19; 19; 7)	128.22 mEq/L Standard Deviation 5.27	130.85 mEq/L Standard Deviation 5.88	127.21 mEq/L Standard Deviation 5.24
Change From Baseline in Serum Sodium Level at Each Time Point Through the 48 Hour Assessment Change at Hour 12 (N=19; 19; 7)	1.78 mEq/L Standard Deviation 3.44	4.65 mEq/L Standard Deviation 4.06	0.73 mEq/L Standard Deviation 3.92
Change From Baseline in Serum Sodium Level at Each Time Point Through the 48 Hour Assessment Hour 16 (N=19; 17; 7)	129.34 mEq/L Standard Deviation 4.51	131.04 mEq/L Standard Deviation 5.07	127.57 mEq/L Standard Deviation 3.78
Change From Baseline in Serum Sodium Level at Each Time Point Through the 48 Hour Assessment Change at Hour 16 (N=19; 17; 7)	2.90 mEq/L Standard Deviation 3.46	4.93 mEq/L Standard Deviation 3.28	1.09 mEq/L Standard Deviation 2.69
Change From Baseline in Serum Sodium Level at Each Time Point Through the 48 Hour Assessment Hour 24 (N=18; 16; 8)	128.87 mEq/L Standard Deviation 4.73	130.74 mEq/L Standard Deviation 5.33	127.48 mEq/L Standard Deviation 3.62
Change From Baseline in Serum Sodium Level at Each Time Point Through the 48 Hour Assessment Change at Hour 24 (N=18; 16; 8)	2.66 mEq/L Standard Deviation 3.76	4.62 mEq/L Standard Deviation 3.59	1.05 mEq/L Standard Deviation 2.73
Change From Baseline in Serum Sodium Level at Each Time Point Through the 48 Hour Assessment Hour 28 (N=19; 17; 8)	130.79 mEq/L Standard Deviation 4.94	131.62 mEq/L Standard Deviation 4.52	126.49 mEq/L Standard Deviation 4.03
Change From Baseline in Serum Sodium Level at Each Time Point Through the 48 Hour Assessment Change at Hour 28 (N=19; 17; 8)	4.35 mEq/L Standard Deviation 3.80	5.51 mEq/L Standard Deviation 2.75	0.06 mEq/L Standard Deviation 3.30
Change From Baseline in Serum Sodium Level at Each Time Point Through the 48 Hour Assessment Hour 36 (N=19; 15; 8)	131.42 mEq/L Standard Deviation 4.99	132.47 mEq/L Standard Deviation 5.04	127.31 mEq/L Standard Deviation 3.05
Change From Baseline in Serum Sodium Level at Each Time Point Through the 48 Hour Assessment Change at Hour 36 (N=19; 15; 8)	4.98 mEq/L Standard Deviation 3.73	6.54 mEq/L Standard Deviation 3.28	0.89 mEq/L Standard Deviation 2.55
Change From Baseline in Serum Sodium Level at Each Time Point Through the 48 Hour Assessment Hour 40 (N=19; 16; 8)	130.83 mEq/L Standard Deviation 5.04	132.23 mEq/L Standard Deviation 3.99	127.00 mEq/L Standard Deviation 1.85
Change From Baseline in Serum Sodium Level at Each Time Point Through the 48 Hour Assessment Change at Hour 40 (N=19; 16; 8)	4.39 mEq/L Standard Deviation 3.44	6.30 mEq/L Standard Deviation 3.27	0.58 mEq/L Standard Deviation 1.66
Change From Baseline in Serum Sodium Level at Each Time Point Through the 48 Hour Assessment Hour 48 (N=19; 17; 8)	130.44 mEq/L Standard Deviation 5.21	133.35 mEq/L Standard Deviation 4.82	127.59 mEq/L Standard Deviation 2.36
Change From Baseline in Serum Sodium Level at Each Time Point Through the 48 Hour Assessment Change at Hour 48 (N=19; 17; 8)	4.00 mEq/L Standard Deviation 3.80	7.36 mEq/L Standard Deviation 4.04	1.16 mEq/L Standard Deviation 2.86

SECONDARY outcome

Timeframe: 48 Hours

Population: Full Analysis Set (FAS): all randomized patients who received at least one dose of study drug and who had baseline serum sodium data.

Confirmed sodium levels refers to two consecutive increases from baseline in sodium of \>4 mEq/L; baseline is the average of the two most recent serum sodium levels prior to start of dosing on day 1. The endpoint was not evaluable in the placebo arm (median and interquartile range cannot be estimated) or the conivaptan QD arm (interquartile range cannot be estimated) because too high a percentage of patients were censored for the event. Only the conivaptan BID arm will be reported.

Outcome measures

Outcome measures
Measure	Regimen 1 Conivaptan QD n=20 Participants 20 mg conivaptan once a day	Regimen 2 Conivaptan BID 20 mg conivaptan two times a day	Regimen 3 Placebo
Time From the First Dose of Study Medication to a Confirmed >4 mEq/L Increase From Baseline in Serum Sodium	16.43 Hours Interval 12.0 to 32.0	—	—

SECONDARY outcome

Timeframe: 48 Hours

Population: Full Analysis Set (FAS): all randomized patients who received at least one dose of study drug and who had baseline serum sodium data.

Confirmed sodium levels refers to two consecutive increases from baseline in sodium of \>4 mEq/L; baseline is the average of the two most recent serum sodium levels prior to start of dosing on day 1.

Outcome measures

Outcome measures
Measure	Regimen 1 Conivaptan QD n=20 Participants 20 mg conivaptan once a day	Regimen 2 Conivaptan BID n=20 Participants 20 mg conivaptan two times a day	Regimen 3 Placebo n=9 Participants
Number of Patients With Confirmed Serum Sodium Level > 4 mEq/L Increase From Baseline Over 0 to 48 Hours	12 Patients	17 Patients	2 Patients

SECONDARY outcome

Timeframe: 48 Hours

Population: Full Analysis Set (FAS): all randomized patients who received at least one dose of study drug and who had baseline serum sodium data.

Confirmed sodium levels refers to two consecutive increases from baseline in sodium of \>6 mEq/L or two consecutive measurements \>135 mEq/L; baseline is the average of the two most recent serum sodium levels prior to start of dosing on day 1.

Outcome measures

Outcome measures
Measure	Regimen 1 Conivaptan QD n=20 Participants 20 mg conivaptan once a day	Regimen 2 Conivaptan BID n=20 Participants 20 mg conivaptan two times a day	Regimen 3 Placebo n=9 Participants
Number of Patients With Confirmed Serum Sodium Level Increase >6 mEq/L From Baseline or Confirmed Normal Serum Sodium Level (>135 mEq/L) Over the Duration 0 to 48 Hours	6 Patients	11 Patients	0 Patients

SECONDARY outcome

Timeframe: 48 Hours

Population: Full Analysis Set (FAS): all randomized patients who received at least one dose of study drug and who had baseline serum sodium data.

Each individual subject's change from baseline serum sodium levels was used to calculate baseline adjusted area under the curve serum sodium levels for a duration of Time 0 to Time t in hours (labeled as AUC(Na)(0-t). The last available serum sodium level prior to dosing on Day 1 was used as baseline. "t"=48 Hours

Outcome measures

Outcome measures
Measure	Regimen 1 Conivaptan QD n=20 Participants 20 mg conivaptan once a day	Regimen 2 Conivaptan BID n=20 Participants 20 mg conivaptan two times a day	Regimen 3 Placebo n=9 Participants
Baseline -Adjusted Area Under the Curve (AUC) in Serum Sodium Over the Duration 0 to 48 Hours	142.72 Hour * mEq/L Standard Deviation 132.94	244.17 Hour * mEq/L Standard Deviation 142.64	23.21 Hour * mEq/L Standard Deviation 91.49

SECONDARY outcome

Timeframe: Baseline, Hour 12, Hour 24,Hour 36 and Hour 48

Effective water clearence (EWC) was calculated as EWC=V(1-(Una+Uk)/(Pna+Pk)), where V is urine volume, Una is the urine sodium concentration, Uk is the urine potassium concentration, Pna is the serum/plasma sodium concentration, an Pk is the serum /plasma potassium concentration. Baseline is the average of the two most recent serum sodium levels prior to start of dosing on day 1. Hour 48: Hour 48 or time that ended study participation prior to the hour 48 assessment. Change is calculated as Actual Data for each time point - Baseline

Outcome measures

Outcome measures
Measure	Regimen 1 Conivaptan QD n=20 Participants 20 mg conivaptan once a day	Regimen 2 Conivaptan BID n=20 Participants 20 mg conivaptan two times a day	Regimen 3 Placebo n=9 Participants
Change From Baseline in Effective Water Clearance (EWC) at Each Time Point Through the 48-hour Assessment Baseline (N=16; 12; 6)	6.76 mL Standard Deviation 47.91	39.86 mL Standard Deviation 245.23	18.66 mL Standard Deviation 45.05
Change From Baseline in Effective Water Clearance (EWC) at Each Time Point Through the 48-hour Assessment Hour 12 (N=14; 12; 5)	355.65 mL Standard Deviation 684.35	405.21 mL Standard Deviation 744.88	136.22 mL Standard Deviation 154.94
Change From Baseline in Effective Water Clearance (EWC) at Each Time Point Through the 48-hour Assessment Change at Hour 12 (N=12;12; 4)	301.52 mL Standard Deviation 671.78	365.35 mL Standard Deviation 699.96	135.44 mL Standard Deviation 123.36
Change From Baseline in Effective Water Clearance (EWC) at Each Time Point Through the 48-hour Assessment Hour 24 (N=14; 12; 6)	-50.19 mL Standard Deviation 794.22	-261.27 mL Standard Deviation 1009.24	368.01 mL Standard Deviation 688.81
Change From Baseline in Effective Water Clearance (EWC) at Each Time Point Through the 48-hour Assessment Change at Hour 24 (N=13; 11; 5)	-70.61 mL Standard Deviation 796.01	-391.76 mL Standard Deviation 1206.39	383.73 mL Standard Deviation 723.33
Change From Baseline in Effective Water Clearance (EWC) at Each Time Point Through the 48-hour Assessment Hour 36 (N=15; 11; 6)	36.85 mL Standard Deviation 905.18	12.66 mL Standard Deviation 743.24	726.96 mL Standard Deviation 1013.78
Change From Baseline in Effective Water Clearance (EWC) at Each Time Point Through the 48-hour Assessment Change at Hour 36 (N=12; 8; 5)	-91.07 mL Standard Deviation 912.66	-89.12 mL Standard Deviation 805.36	810.45 mL Standard Deviation 1079.89
Change From Baseline in Effective Water Clearance (EWC) at Each Time Point Through the 48-hour Assessment Hour 48 (N=14; 11; 5)	-77.37 mL Standard Deviation 1169.30	-179.37 mL Standard Deviation 852.58	569.09 mL Standard Deviation 1392.07
Change From Baseline in Effective Water Clearance (EWC) at Each Time Point Through the 48-hour Assessment Change at Hour 48 (N=12; 10; 4)	80.23 mL Standard Deviation 1116.99	-240.39 mL Standard Deviation 759.82	690.98 mL Standard Deviation 2872.2

SECONDARY outcome

Timeframe: Baseline, Hour 24 and Hour 48

Free water clearance (FWC) was calculated as FWC=V(1-Uosm/Posm), where V is urine volume, Uosm is the urine osmolality, Posm is the plasma sodium osmolality. Baseline is the average of the two most recent serum sodium levels prior to start of dosing on day 1. Hour 48: Hour 48 or time that ended study participation prior to the hour 48 assessment. Change is calculated as Actual Data for each time point - Baseline

Outcome measures

Outcome measures
Measure	Regimen 1 Conivaptan QD n=20 Participants 20 mg conivaptan once a day	Regimen 2 Conivaptan BID n=20 Participants 20 mg conivaptan two times a day	Regimen 3 Placebo n=9 Participants
Change From Baseline in Free Water Clearance (FWC) at Each Time Point Through the 48-hour Assessment Hour 48 (N=14;12; 5)	-1243.39 mL Standard Deviation 2211.22	-769.19 mL Standard Deviation 934.31	-592.96 mL Standard Deviation 1050.94
Change From Baseline in Free Water Clearance (FWC) at Each Time Point Through the 48-hour Assessment Change at Hour 48 (N=11; 10; 4)	-1313.98 mL Standard Deviation 2477.39	-603.67 mL Standard Deviation 761.90	-702.11 mL Standard Deviation 1117.92
Change From Baseline in Free Water Clearance (FWC) at Each Time Point Through the 48-hour Assessment Baseline (N=14; 11; 6)	-53.87 mL Standard Deviation 45.47	6.55 mL Standard Deviation 165.07	-34.90 mL Standard Deviation 74.32
Change From Baseline in Free Water Clearance (FWC) at Each Time Point Through the 48-hour Assessment Hour 24 (N=14; 12; 6)	-972.29 mL Standard Deviation 1455.66	-611.14 mL Standard Deviation 693.863	-416.71 mL Standard Deviation 666.97
Change From Baseline in Free Water Clearance (FWC) at Each Time Point Through the 48-hour Assessment Change at Hour 24 (N=11; 10; 5)	-936.99 mL Standard Deviation 1618.46	-513.33 mL Standard Deviation 566.72	-420.75 mL Standard Deviation 747.84

Adverse Events

Regimen 1 Conivaptan QD

Serious events: 6 serious events

Other events: 7 other events

Deaths: 0 deaths

Regimen 2 Conivaptan BID

Serious events: 5 serious events

Other events: 10 other events

Deaths: 0 deaths

Regimen 3 Placebo

Serious events: 2 serious events

Other events: 5 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Senior Medical Director, Medical Affairs

Astellas Pharma Global Development

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Institute and/or Principal Investigator may publish trial data generated at their specific study site after Sponsor publication of the multi-center data. Sponsor must receive a site's manuscript at least 30 days prior to publication to ensure that no confidential information of Sponsor is included in the document. Sponsor may delay the publication for an additional 60 days to seek patent protection.
Publication restrictions are in place

Restriction type: OTHER

Measure	Regimen 1 Conivaptan QD n=20 participants at risk 20 mg conivaptan once a day	Regimen 2 Conivaptan BID n=20 participants at risk 20 mg conivaptan two times a day	Regimen 3 Placebo n=9 participants at risk
Blood and lymphatic system disorders Coagulopathy	5.0% 1/20 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.	0.00% 0/20 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.	0.00% 0/9 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.
Cardiac disorders Cardiac failure congestive	10.0% 2/20 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.	5.0% 1/20 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.	0.00% 0/9 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.
Gastrointestinal disorders Ileus	0.00% 0/20 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.	0.00% 0/20 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.	11.1% 1/9 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.
General disorders Multi-organ failure	5.0% 1/20 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.	0.00% 0/20 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.	0.00% 0/9 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.
Infections and infestations Clostridium difficile colitis	0.00% 0/20 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.	0.00% 0/20 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.	11.1% 1/9 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.
Infections and infestations Pneumonia	0.00% 0/20 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.	5.0% 1/20 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.	0.00% 0/9 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.
Metabolism and nutrition disorders Hyperkalaemia	0.00% 0/20 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.	0.00% 0/20 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.	11.1% 1/9 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.
Metabolism and nutrition disorders Hyponatraemia	5.0% 1/20 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.	0.00% 0/20 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.	0.00% 0/9 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.
Nervous system disorders Transient ischaemic attack	5.0% 1/20 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.	0.00% 0/20 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.	0.00% 0/9 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.
Psychiatric disorders Delirium	0.00% 0/20 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.	0.00% 0/20 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.	11.1% 1/9 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.
Renal and urinary disorders Renal failure	5.0% 1/20 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.	0.00% 0/20 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.	0.00% 0/9 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.
Renal and urinary disorders Renal failure acute	0.00% 0/20 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.	0.00% 0/20 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.	11.1% 1/9 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.
Respiratory, thoracic and mediastinal disorders Respiratory acidosis	0.00% 0/20 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.	5.0% 1/20 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.	0.00% 0/9 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.
Respiratory, thoracic and mediastinal disorders Respiratory distress	5.0% 1/20 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.	0.00% 0/20 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.	0.00% 0/9 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.
Surgical and medical procedures Coronary artery bypass	0.00% 0/20 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.	5.0% 1/20 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.	0.00% 0/9 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.
Vascular disorders Hypotension	0.00% 0/20 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.	5.0% 1/20 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.	0.00% 0/9 An Adverse Event was defined as treatment emergent if it occurred after the first dose of study drug through the ninth day after the last dose. Participants at Risk represent the Safety Analysis Set.