Trial Outcomes & Findings for International, Multicenter, Study of One-year, Open-label, Titrated Oral Tolvaptan Tablet Administration in Patients With Chronic Hyponatremia (NCT NCT02449044)

NCT ID: NCT02449044

Last Updated: 2016-01-21

Results Overview

A TEAE was an AE that began after the first injection or was continuous from Baseline and was defined as any new medical problem, or exacerbation of an existing problem, whether or not it was considered drug-related by the study physician. An AE was considered serious if it was fatal; life-threatening; persistently or significantly disabling or incapacitating; required in-subject hospitalization or prolonged hospitalization; a congenital anomaly/birth defect; or other medically significant event that, based upon appropriate medical judgment, may have jeopardized the participant and may have required medical or surgical intervention to prevent the outcomes mentioned above.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 111 participants
• Primary outcome timeframe: Baseline to Post-Week 214 follow-up visit
• Results posted on: 2016-01-21

Participant Flow

The trial was conducted in 111 enrolled participants at 33 trial centers. This is an extension study of trials NCT00072683 and NCT00201994. Approximately 50% participants may have been on tolvaptan previously, there was a minimum 7-day period off treatment between trials.

Participants were blinded prior to treatment with tolvaptan with titration between target doses of 15mg, 30mg or 60mg of study drug was based on the participant's response in serum sodium concentration and clinical tolerance of study drug. Dose titration aim was to stabilize the participants with normal range of blood sodium.

Participant milestones

Measure	Tolvaptan Participants received 15 mg tolvaptan QD and were titrated from 15mg, 30mg, or 60mg of tolvaptan based on the participant's response in serum sodium concentration and clinical tolerance of study drug.
Overall Study STARTED	111
Overall Study COMPLETED	47
Overall Study NOT COMPLETED	64

Reasons for withdrawal

Measure	Tolvaptan Participants received 15 mg tolvaptan QD and were titrated from 15mg, 30mg, or 60mg of tolvaptan based on the participant's response in serum sodium concentration and clinical tolerance of study drug.
Overall Study Lost to Follow-up	2
Overall Study Withdrawal by Subject	13
Overall Study Adverse Event	30
Overall Study Met Withdrawal Criteria	7
Overall Study Physician Decision	9
Overall Study Sponsor Discontinued Trial	3

Baseline Characteristics

International, Multicenter, Study of One-year, Open-label, Titrated Oral Tolvaptan Tablet Administration in Patients With Chronic Hyponatremia

Baseline characteristics by cohort

Measure	Tolvaptan n=111 Participants Participants received 15 mg tolvaptan QD and were titrated from 15mg, 30mg, or 60mg of tolvaptan based on the participant's response in serum sodium concentration and clinical tolerance of study drug.
Age, Continuous	64.6 Years STANDARD_DEVIATION 15.0 • n=5 Participants
Sex: Female, Male Female	56 Participants n=5 Participants
Sex: Female, Male Male	55 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline to Post-Week 214 follow-up visit

Population: The ITT dataset, which comprised of data from all enrolled participants who had observations at Baseline and at least one Post-Baseline visit, were analyzed.

A TEAE was an AE that began after the first injection or was continuous from Baseline and was defined as any new medical problem, or exacerbation of an existing problem, whether or not it was considered drug-related by the study physician. An AE was considered serious if it was fatal; life-threatening; persistently or significantly disabling or incapacitating; required in-subject hospitalization or prolonged hospitalization; a congenital anomaly/birth defect; or other medically significant event that, based upon appropriate medical judgment, may have jeopardized the participant and may have required medical or surgical intervention to prevent the outcomes mentioned above.

Outcome measures

Measure	Tolvaptan n=111 Participants Participants received 15 mg tolvaptan QD and were titrated from 15mg, 30mg, or 60mg of tolvaptan based on the participant's response in serum sodium concentration and clinical tolerance of study drug.
Participants With Adverse Events (AEs) Participants discontinued IMP due to TEAE/death	28 participants
Participants With Adverse Events (AEs) Participants with TEAEs	105 participants
Participants With Adverse Events (AEs) Participants with serious TEAEs	76 participants
Participants With Adverse Events (AEs) Participants with severe TEAEs	73 participants
Participants With Adverse Events (AEs) Participants discontinued IMP due to TEAE	19 participants
Participants With Adverse Events (AEs) Deaths	19 participants

PRIMARY outcome

Timeframe: Baseline to Post-Week 214 follow-up visit

Population: The ITT dataset, which comprised of data from all enrolled participants who had observations at Baseline and at least one Post-Baseline visit, were analyzed.

The laboratory values were one of the primary parameters to measure the safety and tolerability of individual participants. Incidence of TEAEs of potential clinical relevance include abnormal values in serum chemistry, hematology, urinalyses and prolactin tests that were identified based on pre-defined criteria. Any value outside the normal range was flagged for the attention of the study physician who was to indicate whether the value was clinically significant for identifying laboratory values of potential clinical relevance. Participants noted with abnormal laboratory values are reported below.

Outcome measures

Measure	Tolvaptan n=111 Participants Participants received 15 mg tolvaptan QD and were titrated from 15mg, 30mg, or 60mg of tolvaptan based on the participant's response in serum sodium concentration and clinical tolerance of study drug.
Participants With Laboratory Values Abnormalities Reported as TEAEs Serum Chemistry-Hepatic enzyme increased	2 participants
Participants With Laboratory Values Abnormalities Reported as TEAEs Serum Chemistry-Hyperuricaemia	3 participants
Participants With Laboratory Values Abnormalities Reported as TEAEs Serum Chemistry-Hypoglycaemia	5 participants
Participants With Laboratory Values Abnormalities Reported as TEAEs Serum Chemistry-Hypokalaemia	14 participants
Participants With Laboratory Values Abnormalities Reported as TEAEs Serum Chemistry-Hypomagnesaemia	3 participants
Participants With Laboratory Values Abnormalities Reported as TEAEs Serum Chemistry-Hypoatraemia	25 participants
Participants With Laboratory Values Abnormalities Reported as TEAEs Hematology-Anemia	20 participants
Participants With Laboratory Values Abnormalities Reported as TEAEs Hematology-Thrombocytopenia	2 participants
Participants With Laboratory Values Abnormalities Reported as TEAEs Hematology-International normalized ratioincreased	4 participants
Participants With Laboratory Values Abnormalities Reported as TEAEs Hematology-White blood cell count increased	2 participants
Participants With Laboratory Values Abnormalities Reported as TEAEs Serum Chemistry-Hyperkalaemia	7 participants
Participants With Laboratory Values Abnormalities Reported as TEAEs Serum Chemistry-Blood creatinine increased	4 participants
Participants With Laboratory Values Abnormalities Reported as TEAEs Serum Chemistry-Blood potassium increased	4 participants
Participants With Laboratory Values Abnormalities Reported as TEAEs Serum Chemistry-Blood glucose increased	3 participants
Participants With Laboratory Values Abnormalities Reported as TEAEs Serum Chemistry-Blood potassium decreased	3 participants
Participants With Laboratory Values Abnormalities Reported as TEAEs SerumChemistry-Aspartate aminotransferaseincreased	2 participants
Participants With Laboratory Values Abnormalities Reported as TEAEs Serum Chemistry-Blood cholesterol increased	3 participants
Participants With Laboratory Values Abnormalities Reported as TEAEs Serum Chemistry-Blood sodium increased	2 participants
Participants With Laboratory Values Abnormalities Reported as TEAEs Serum Chemistry-Oxygen saturation decreased	2 participants
Participants With Laboratory Values Abnormalities Reported as TEAEs Serum Chemistry-Hyperglycaemia	5 participants
Participants With Laboratory Values Abnormalities Reported as TEAEs Serum Chemistry-Hyperlipidaemia	4 participants
Participants With Laboratory Values Abnormalities Reported as TEAEs Serum Chemistry-Hypernatraemia	4 participants

PRIMARY outcome

Timeframe: Baseline to Post-Week 214 follow-up visit

Population: The ITT dataset, which comprised of data from all enrolled participants who had observations at Baseline and at least one Post-Baseline visit, were analyzed.

The ECG was one of the primary parameters to measure the safety and tolerability of individual participants. Incidence of TEAEs of potential clinical relevance included abnormal values in HR outliers, PR outliers, QRS outliers, QT, QTcB, QTcF that were identified based on pre-defined criteria. Some of the pre-defined criteria for identifying ECG measurements of potential clinical relevance included: For QTcB and QTcF: baseline mean of QTcB and QTcF interval was new onset >500 msec, 30 - 60 msec, >60 msec; For QT: new onset >500 msec; For QRS outliers: >=25% change from baseline when QRS >100 msec; PR outliers: >=25% change from baseline when PR>200 msec; HR outliers: 25% decrease from baseline and HR <50 bpm or 25% increase from baseline and HR >100 bpm. New onset (>500 msec) in QT, QTcB, or QTcF means a participant who attained a value >500 msec during treatment period but not at each baseline visit. The ECG-related abnormalities are reported as TEAEs are mentioned below.

Outcome measures

Measure	Tolvaptan n=111 Participants Participants received 15 mg tolvaptan QD and were titrated from 15mg, 30mg, or 60mg of tolvaptan based on the participant's response in serum sodium concentration and clinical tolerance of study drug.
Participants With Electrocardiogram (ECG) Related Abnormalities Reported as TEAEs Atrial fibrillation	6 participants
Participants With Electrocardiogram (ECG) Related Abnormalities Reported as TEAEs Tachycardia	4 participants
Participants With Electrocardiogram (ECG) Related Abnormalities Reported as TEAEs Atrial tachycardia	3 participants
Participants With Electrocardiogram (ECG) Related Abnormalities Reported as TEAEs First degree atrioventricular block	2 participants
Participants With Electrocardiogram (ECG) Related Abnormalities Reported as TEAEs Bradycardia	2 participants
Participants With Electrocardiogram (ECG) Related Abnormalities Reported as TEAEs Sinus tachycardia	2 participants
Participants With Electrocardiogram (ECG) Related Abnormalities Reported as TEAEs Ventricular tachycardia	2 participants
Participants With Electrocardiogram (ECG) Related Abnormalities Reported as TEAEs Left bundle branch block	1 participants
Participants With Electrocardiogram (ECG) Related Abnormalities Reported as TEAEs Tachyarrhythmia	1 participants
Participants With Electrocardiogram (ECG) Related Abnormalities Reported as TEAEs Ventricular arrhythmia	1 participants
Participants With Electrocardiogram (ECG) Related Abnormalities Reported as TEAEs Atrial flutter	1 participants
Participants With Electrocardiogram (ECG) Related Abnormalities Reported as TEAEs ECG ST segment depression	1 participants
Participants With Electrocardiogram (ECG) Related Abnormalities Reported as TEAEs Arrhythmia	1 participants

PRIMARY outcome

Timeframe: Baseline to Post-Week 214 follow-up visit

Population: The intent-to-treat (ITT) dataset, which comprised of data from all enrolled participants who had observations at Baseline and at least one Post-Baseline visit, were analyzed.

The vital signs were one of the primary parameters to measure the safety and tolerability of individual participants. Incidence of TEAEs of potential clinical relevance included abnormal values in body temperature, heart rate, systolic and diastolic blood pressure, respiratory rate and weight that were identified based on pre-defined criteria. Criteria for identifying vital signs of potential clinical relevance included: Heart rate, supine: >= 120 beats per minute (bpm) + increase of ≥15 bpm from Baseline and <=50 bpm + decrease of >= 15 bpm; Diastolic Blood Pressure, Supine: >=105 mmHg + increase of >=15 mmHg and <=50 mmHg + decrease of >=15 mmHg; Systolic Blood Pressure, Supine: >=180 mmHg + increase of >=20 mmHg and <= 90 mmHg + decrease of >=20 mmHg; Temperature (degree C): Increase of >=1.1 to >=38.3C. The vital sign abnormalities were reported as TEAEs are mentioned below.

Outcome measures

Measure	Tolvaptan n=111 Participants Participants received 15 mg tolvaptan QD and were titrated from 15mg, 30mg, or 60mg of tolvaptan based on the participant's response in serum sodium concentration and clinical tolerance of study drug.
Participants With Vital Signs Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs) Hypotension	13 participants
Participants With Vital Signs Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs) Hypertension	8 participants
Participants With Vital Signs Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs) Pyrexia	6 participants
Participants With Vital Signs Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs) Increased body temperature	3 participants
Participants With Vital Signs Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs) Palpitations	2 participants
Participants With Vital Signs Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs) Increased central venous pressure	2 participants
Participants With Vital Signs Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs) Increased venous pressure	1 participants
Participants With Vital Signs Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs) Orthostatic hypotension	1 participants
Participants With Vital Signs Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs) Hypertensive crisis	1 participants
Participants With Vital Signs Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs) Decreased orthostatic blood pressure	1 participants
Participants With Vital Signs Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs) Increased weight	5 participants
Participants With Vital Signs Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs) Decreased weight	1 participants

PRIMARY outcome

Timeframe: Baseline to Post-Week 214 follow-up visit

Population: The ITT dataset, which comprised of data from all enrolled participants who had observations at Baseline and at least one Post-Baseline visit, were analyzed.

The body weight evaluation was one of the primary parameters to measure the safety and tolerability of individual participants. Every effort was made to ensure that body weight measurements were performed in a reproducible and consistent manner. The pre-defined criteria was change of ≥7% in body weight for both male and female. Participants were to wear the same type of clothes at each measurement, preferably a gown and no shoes. All body weight measurements were to have been taken post-void.

Outcome measures

Measure	Tolvaptan n=111 Participants Participants received 15 mg tolvaptan QD and were titrated from 15mg, 30mg, or 60mg of tolvaptan based on the participant's response in serum sodium concentration and clinical tolerance of study drug.
Participants With Body Weight Abnormalities Reported as TEAEs Increased weight	5 participants
Participants With Body Weight Abnormalities Reported as TEAEs Decreased weight	1 participants

SECONDARY outcome

Timeframe: Baseline of parent trial to Week 214

Population: The ITT dataset, which comprised of data from all enrolled participants who had observations at Baseline and at least one Post-Baseline visit, were analyzed. In the last observation carried forward (LOCF) dataset, missing data were filled in using the participant's preceding non-missing value, except that Baseline value will not be carried forward.

Sodium measurements obtained at designated intervals were compared to each participant's Baseline sodium level at the beginning of placebo-controlled therapy in their original trial and from Baseline on initiation of therapy in the open-label trial.

Outcome measures

Measure	Tolvaptan n=111 Participants Participants received 15 mg tolvaptan QD and were titrated from 15mg, 30mg, or 60mg of tolvaptan based on the participant's response in serum sodium concentration and clinical tolerance of study drug.
Mean Change From Baseline in Serum Sodium Measurements Day 1 post-dose (N= 99)	2.2 mEq/L Standard Deviation 3.3
Mean Change From Baseline in Serum Sodium Measurements Day 14 (N= 110)	5.2 mEq/L Standard Deviation 5.5
Mean Change From Baseline in Serum Sodium Measurements Day 31 (N= 110)	5.0 mEq/L Standard Deviation 4.8
Mean Change From Baseline in Serum Sodium Measurements Week 10 (N= 110)	5.0 mEq/L Standard Deviation 5.1
Mean Change From Baseline in Serum Sodium Measurements Week 18 (N= 110)	4.6 mEq/L Standard Deviation 5.4
Mean Change From Baseline in Serum Sodium Measurements Week 26 (N= 110)	4.2 mEq/L Standard Deviation 5.7
Mean Change From Baseline in Serum Sodium Measurements Week 34 (N= 110)	4.7 mEq/L Standard Deviation 5.9
Mean Change From Baseline in Serum Sodium Measurements Week 42 (N= 110)	5.2 mEq/L Standard Deviation 5.6
Mean Change From Baseline in Serum Sodium Measurements Week 50 (N= 110)	5.0 mEq/L Standard Deviation 5.9
Mean Change From Baseline in Serum Sodium Measurements Week 58 (N= 110)	5.0 mEq/L Standard Deviation 5.9
Mean Change From Baseline in Serum Sodium Measurements Week 70 (N= 110)	4.8 mEq/L Standard Deviation 5.8
Mean Change From Baseline in Serum Sodium Measurements Week 82 (N= 110)	4.8 mEq/L Standard Deviation 5.7
Mean Change From Baseline in Serum Sodium Measurements Week 94 (N= 110)	5.1 mEq/L Standard Deviation 5.8
Mean Change From Baseline in Serum Sodium Measurements Week 106 (N= 110)	5.0 mEq/L Standard Deviation 6.0
Mean Change From Baseline in Serum Sodium Measurements Week 118 (N= 110)	4.8 mEq/L Standard Deviation 5.9
Mean Change From Baseline in Serum Sodium Measurements Week 130 (N= 110)	4.9 mEq/L Standard Deviation 6.0
Mean Change From Baseline in Serum Sodium Measurements Week 142 (N= 110)	5.2 mEq/L Standard Deviation 5.9
Mean Change From Baseline in Serum Sodium Measurements Week 154 (N= 110)	5.2 mEq/L Standard Deviation 5.9
Mean Change From Baseline in Serum Sodium Measurements Week 166 (N= 110)	4.9 mEq/L Standard Deviation 5.8
Mean Change From Baseline in Serum Sodium Measurements Week 178 (N= 110)	4.8 mEq/L Standard Deviation 5.9
Mean Change From Baseline in Serum Sodium Measurements Week 190 (N= 110)	5.1 mEq/L Standard Deviation 6.1
Mean Change From Baseline in Serum Sodium Measurements Week 202 (N= 110)	5.0 mEq/L Standard Deviation 5.9
Mean Change From Baseline in Serum Sodium Measurements Week 214 (N= 110)	5.0 mEq/L Standard Deviation 5.9

SECONDARY outcome

Timeframe: Baseline to Week 214

Population: The ITT dataset, which comprised of data from all enrolled participants who had observations at Baseline and at least one Post-Baseline visit, were analyzed. In the last observation carried forward (LOCF) dataset, missing data were filled in using the participant's preceding non-missing value, except that Baseline value will not be carried forward.

Percentage of participants with varying degrees of hyponatremia ("severe" <130, "mild" 130-135, "normal" >135 mEq/L) at Baseline and each study visit.

Outcome measures

Measure	Tolvaptan n=111 Participants Participants received 15 mg tolvaptan QD and were titrated from 15mg, 30mg, or 60mg of tolvaptan based on the participant's response in serum sodium concentration and clinical tolerance of study drug.
Change From Baseline in Percentage of Participants With Severe Hyponatremia Week 190 (N=110)	11.8 percentage of participants 4.7
Change From Baseline in Percentage of Participants With Severe Hyponatremia Week 202 (N=110)	11.8 percentage of participants 4.6
Change From Baseline in Percentage of Participants With Severe Hyponatremia Week 214 (N=110)	11.8 percentage of participants 4.6
Change From Baseline in Percentage of Participants With Severe Hyponatremia Week 42 (N=110)	12.7 percentage of participants 4.1
Change From Baseline in Percentage of Participants With Severe Hyponatremia Week 50 (N=110)	10.9 percentage of participants 4.5
Change From Baseline in Percentage of Participants With Severe Hyponatremia Week 58 (N=110)	13.6 percentage of participants 5.1
Change From Baseline in Percentage of Participants With Severe Hyponatremia Week 70 (N=110)	12.7 percentage of participants 4.6
Change From Baseline in Percentage of Participants With Severe Hyponatremia Week 82 (N=110)	10.9 percentage of participants 4.1
Change From Baseline in Percentage of Participants With Severe Hyponatremia Week 94 (N=110)	10.9 percentage of participants 4.8
Change From Baseline in Percentage of Participants With Severe Hyponatremia Week 106 (N=110)	12.7 percentage of participants 4.7
Change From Baseline in Percentage of Participants With Severe Hyponatremia Week 118 (N=110)	12.7 percentage of participants 4.4
Change From Baseline in Percentage of Participants With Severe Hyponatremia Week 130 (N=110)	11.8 percentage of participants 4.7
Change From Baseline in Percentage of Participants With Severe Hyponatremia Week 142 (N=110)	11.8 percentage of participants 4.5
Change From Baseline in Percentage of Participants With Severe Hyponatremia Week 154 (N=110)	11.8 percentage of participants 4.4
Change From Baseline in Percentage of Participants With Severe Hyponatremia Week 166 (N=110)	11.8 percentage of participants 4.5
Change From Baseline in Percentage of Participants With Severe Hyponatremia Week 178 (N=110)	11.8 percentage of participants 4.5
Change From Baseline in Percentage of Participants With Severe Hyponatremia Day 1 post-dose (N=99)	20.2 percentage of participants 3.0
Change From Baseline in Percentage of Participants With Severe Hyponatremia Day 31 (N=110)	9.1 percentage of participants 5.1
Change From Baseline in Percentage of Participants With Severe Hyponatremia Week 10 (N=110)	11.8 percentage of participants 5.0
Change From Baseline in Percentage of Participants With Severe Hyponatremia Week 18 (N=110)	13.6 percentage of participants 4.0
Change From Baseline in Percentage of Participants With Severe Hyponatremia Week 26 (N=110)	16.4 percentage of participants 4.6
Change From Baseline in Percentage of Participants With Severe Hyponatremia Week 34 (N=110)	14.5 percentage of participants 5.6

SECONDARY outcome

Timeframe: Baseline to Week 214

Population: The ITT dataset, which comprised of data from all enrolled participants who had observations at Baseline and at least one Post-Baseline visit, were analyzed. In the last observation carried forward (LOCF) dataset, missing data were filled in using the participant's preceding non-missing value, except that Baseline value will not be carried forward.

Percentage of participants with varying degrees of hyponatremia ("severe" <130, "mild" 130-135, "normal" >135 mEq/L) at Baseline and each study visit.

Outcome measures

Measure	Tolvaptan n=111 Participants Participants received 15 mg tolvaptan QD and were titrated from 15mg, 30mg, or 60mg of tolvaptan based on the participant's response in serum sodium concentration and clinical tolerance of study drug.
Change From Baseline in Percentage of Participants With Mild Hyponatremia Day 1 post-dose (N=99)	53.5 percentage of participants
Change From Baseline in Percentage of Participants With Mild Hyponatremia Day 31 (N=110)	33.6 percentage of participants
Change From Baseline in Percentage of Participants With Mild Hyponatremia Week 10 (N=110)	28.2 percentage of participants
Change From Baseline in Percentage of Participants With Mild Hyponatremia Week 18 (N=110)	33.6 percentage of participants
Change From Baseline in Percentage of Participants With Mild Hyponatremia Week 26 (N=110)	30.9 percentage of participants
Change From Baseline in Percentage of Participants With Mild Hyponatremia Week 34 (N=110)	26.4 percentage of participants
Change From Baseline in Percentage of Participants With Mild Hyponatremia Week 42 (N=110)	26.4 percentage of participants
Change From Baseline in Percentage of Participants With Mild Hyponatremia Week 50 (N=110)	31.8 percentage of participants
Change From Baseline in Percentage of Participants With Mild Hyponatremia Week 58 (N=110)	26.4 percentage of participants
Change From Baseline in Percentage of Participants With Mild Hyponatremia Week 70 (N=110)	30.9 percentage of participants
Change From Baseline in Percentage of Participants With Mild Hyponatremia Week 82 (N=110)	31.8 percentage of participants
Change From Baseline in Percentage of Participants With Mild Hyponatremia Week 94 (N=110)	28.2 percentage of participants
Change From Baseline in Percentage of Participants With Mild Hyponatremia Week 106 (N=110)	27.3 percentage of participants
Change From Baseline in Percentage of Participants With Mild Hyponatremia Week 118 (N=110)	28.2 percentage of participants
Change From Baseline in Percentage of Participants With Mild Hyponatremia Week 130 (N=110)	29.1 percentage of participants
Change From Baseline in Percentage of Participants With Mild Hyponatremia Week 142 (N=110)	25.5 percentage of participants
Change From Baseline in Percentage of Participants With Mild Hyponatremia Week 154 (N=110)	25.5 percentage of participants
Change From Baseline in Percentage of Participants With Mild Hyponatremia Week 166 (N=110)	30.9 percentage of participants
Change From Baseline in Percentage of Participants With Mild Hyponatremia Week 178 (N=110)	30.9 percentage of participants
Change From Baseline in Percentage of Participants With Mild Hyponatremia Week 190 (N=110)	30.9 percentage of participants
Change From Baseline in Percentage of Participants With Mild Hyponatremia Week 202 (N=110)	30.9 percentage of participants
Change From Baseline in Percentage of Participants With Mild Hyponatremia Week 214 (N=110)	30.9 percentage of participants

SECONDARY outcome

Timeframe: Baseline to Week 214

Population: The ITT dataset, which comprised of data from all enrolled participants who had observations at Baseline and at least one Post-Baseline visit, were analyzed. In the last observation carried forward (LOCF) dataset, missing data were filled in using the participant's preceding non-missing value, except that Baseline value will not be carried forward.

Percentage of participants with varying degrees of hyponatremia ("severe" <130, "mild" 130-135, "normal" >135 mEq/L) at Baseline and each study visit.

Outcome measures

Measure	Tolvaptan n=111 Participants Participants received 15 mg tolvaptan QD and were titrated from 15mg, 30mg, or 60mg of tolvaptan based on the participant's response in serum sodium concentration and clinical tolerance of study drug.
Change From Baseline in Percentage of Participants With Normal Sodium Levels Day 1 post-dose (N=99)	26.3 percentage of participants
Change From Baseline in Percentage of Participants With Normal Sodium Levels Day 31 (N=110)	57.3 percentage of participants
Change From Baseline in Percentage of Participants With Normal Sodium Levels Week 10 (N=110)	60.0 percentage of participants
Change From Baseline in Percentage of Participants With Normal Sodium Levels Week 18 (N=110)	52.7 percentage of participants
Change From Baseline in Percentage of Participants With Normal Sodium Levels Week 26 (N=110)	52.7 percentage of participants
Change From Baseline in Percentage of Participants With Normal Sodium Levels Week 34 (N=110)	59.1 percentage of participants
Change From Baseline in Percentage of Participants With Normal Sodium Levels Week 42 (N=110)	60.9 percentage of participants
Change From Baseline in Percentage of Participants With Normal Sodium Levels Week 50 (N=110)	57.3 percentage of participants
Change From Baseline in Percentage of Participants With Normal Sodium Levels Week 58 (N=110)	60.0 percentage of participants
Change From Baseline in Percentage of Participants With Normal Sodium Levels Week 70 (N=110)	56.4 percentage of participants
Change From Baseline in Percentage of Participants With Normal Sodium Levels Week 82 (N=110)	57.3 percentage of participants
Change From Baseline in Percentage of Participants With Normal Sodium Levels Week 94 (N=110)	60.9 percentage of participants
Change From Baseline in Percentage of Participants With Normal Sodium Levels Week 106 (N=110)	60.0 percentage of participants
Change From Baseline in Percentage of Participants With Normal Sodium Levels Week 118 (N=110)	59.1 percentage of participants
Change From Baseline in Percentage of Participants With Normal Sodium Levels Week 130 (N=110)	59.1 percentage of participants
Change From Baseline in Percentage of Participants With Normal Sodium Levels Week 142 (N=110)	62.7 percentage of participants
Change From Baseline in Percentage of Participants With Normal Sodium Levels Week 154 (N=110)	62.7 percentage of participants
Change From Baseline in Percentage of Participants With Normal Sodium Levels Week 166 (N=110)	57.3 percentage of participants
Change From Baseline in Percentage of Participants With Normal Sodium Levels Week 178 (N=110)	57.3 percentage of participants
Change From Baseline in Percentage of Participants With Normal Sodium Levels Week 190 (N=110)	57.3 percentage of participants
Change From Baseline in Percentage of Participants With Normal Sodium Levels Week 202 (N=110)	58.2 percentage of participants
Change From Baseline in Percentage of Participants With Normal Sodium Levels Week 214 (N=110)	57.3 percentage of participants

SECONDARY outcome

Timeframe: Baseline to Post-Week 214 follow-up visit

Population: The ITT dataset, which comprised of data from all enrolled participants who had observations at Baseline and at least one Post-Baseline visit, were analyzed. In the last observation carried forward (LOCF) dataset, missing data were filled in using the participant's preceding non-missing value, except that Baseline value will not be carried forward.

Percentage of participants requiring prescription of fluid restriction for the express purpose of treating hyponatremia during each period of the trial. Assessed descriptively at each visit.

Outcome measures

Measure	Tolvaptan n=111 Participants Participants received 15 mg tolvaptan QD and were titrated from 15mg, 30mg, or 60mg of tolvaptan based on the participant's response in serum sodium concentration and clinical tolerance of study drug.
Percentage of Participants Requiring Prescription of Fluid Restriction Mild Hyponatremia (N=76)	14.47 percentage of participants
Percentage of Participants Requiring Prescription of Fluid Restriction Severe Hyponatremia (N=35)	5.71 percentage of participants

SECONDARY outcome

Timeframe: Baseline to Post-Week 214 follow-up visit

Population: The ITT dataset, which comprised of data from all enrolled participants who had observations at Baseline and at least one Post-Baseline visit, were analyzed. Percentage of participants requiring prescription of hypertonic saline was not analyzed due to a low number of participants who received the treatment.

Percentage of participants requiring prescription of hypertonic saline for the express purpose of treating hyponatremia during each period of the trial, assessed descriptively at each visit.

Outcome measures

Measure	Tolvaptan n=111 Participants Participants received 15 mg tolvaptan QD and were titrated from 15mg, 30mg, or 60mg of tolvaptan based on the participant's response in serum sodium concentration and clinical tolerance of study drug.
Number of Participants Requiring Prescription of Hypertonic Saline	2 participants

SECONDARY outcome

Timeframe: Baseline to Post-Week 214 follow-up visit

Population: The ITT dataset, which comprised of data from all enrolled participants who had observations at Baseline and at least one Post-Baseline visit, were analyzed. Percentage of participants requiring other medicines such as demeclocycline or urea was not analyzed.

Percentage of participants requiring prescription of other medicines for the express purpose of treating hyponatremia during each period of the trial, assessed descriptively at each visit.

Outcome measures

Measure	Tolvaptan n=111 Participants Participants received 15 mg tolvaptan QD and were titrated from 15mg, 30mg, or 60mg of tolvaptan based on the participant's response in serum sodium concentration and clinical tolerance of study drug.
Percentage of Participants Requiring Prescription of Other Medicines	0 percentage of participants

SECONDARY outcome

Timeframe: Baseline to Week 214

Population: The ITT dataset comprised of data from all enrolled participants who had observations at Baseline and at least one Post-Baseline visit were analyzed. The observed cases (OC) dataset consisted of only data points obtained from participants who were evaluated at the visit, without missing study drug consecutively for 14 days.

Body weight at each visit (assessed only for those with clinical evidence of hypervolemia at Baseline) and was summarized using descriptive statistics.

Outcome measures

Measure	Tolvaptan n=111 Participants Participants received 15 mg tolvaptan QD and were titrated from 15mg, 30mg, or 60mg of tolvaptan based on the participant's response in serum sodium concentration and clinical tolerance of study drug.
Mean Change From Baseline in Body Weight by Visit for Those Participants Who Had Clinical Evidence of Hypervolemia at Baseline Week 202 (N= 2)	-7.1 kg Standard Deviation 0.4
Mean Change From Baseline in Body Weight by Visit for Those Participants Who Had Clinical Evidence of Hypervolemia at Baseline Week 214 (N= 2)	-8.5 kg Standard Deviation 1.6
Mean Change From Baseline in Body Weight by Visit for Those Participants Who Had Clinical Evidence of Hypervolemia at Baseline Day 31 (N= 26)	-0.5 kg Standard Deviation 4.6
Mean Change From Baseline in Body Weight by Visit for Those Participants Who Had Clinical Evidence of Hypervolemia at Baseline Week 10 (N= 32)	-1.1 kg Standard Deviation 3.7
Mean Change From Baseline in Body Weight by Visit for Those Participants Who Had Clinical Evidence of Hypervolemia at Baseline Week 18 (N= 27)	0.2 kg Standard Deviation 3.0
Mean Change From Baseline in Body Weight by Visit for Those Participants Who Had Clinical Evidence of Hypervolemia at Baseline Week 26 (N= 27)	0.4 kg Standard Deviation 5.4
Mean Change From Baseline in Body Weight by Visit for Those Participants Who Had Clinical Evidence of Hypervolemia at Baseline Week 34 (N= 26)	0.5 kg Standard Deviation 4.0
Mean Change From Baseline in Body Weight by Visit for Those Participants Who Had Clinical Evidence of Hypervolemia at Baseline Week 42 (N= 24)	0.3 kg Standard Deviation 4.6
Mean Change From Baseline in Body Weight by Visit for Those Participants Who Had Clinical Evidence of Hypervolemia at Baseline Week 50 (N= 22)	1.0 kg Standard Deviation 4.7
Mean Change From Baseline in Body Weight by Visit for Those Participants Who Had Clinical Evidence of Hypervolemia at Baseline Week 58 (N= 22)	1.7 kg Standard Deviation 4.5
Mean Change From Baseline in Body Weight by Visit for Those Participants Who Had Clinical Evidence of Hypervolemia at Baseline Week 70 (N= 18)	1.7 kg Standard Deviation 5.2
Mean Change From Baseline in Body Weight by Visit for Those Participants Who Had Clinical Evidence of Hypervolemia at Baseline Week 82 (N= 18)	2.0 kg Standard Deviation 7.0
Mean Change From Baseline in Body Weight by Visit for Those Participants Who Had Clinical Evidence of Hypervolemia at Baseline Week 94 (N= 18)	3.0 kg Standard Deviation 8.0
Mean Change From Baseline in Body Weight by Visit for Those Participants Who Had Clinical Evidence of Hypervolemia at Baseline Week 106 (N= 15)	1.4 kg Standard Deviation 8.0
Mean Change From Baseline in Body Weight by Visit for Those Participants Who Had Clinical Evidence of Hypervolemia at Baseline Week 118 (N= 13)	2.2 kg Standard Deviation 8.1
Mean Change From Baseline in Body Weight by Visit for Those Participants Who Had Clinical Evidence of Hypervolemia at Baseline Week 130 (N= 13)	3.0 kg Standard Deviation 9.0
Mean Change From Baseline in Body Weight by Visit for Those Participants Who Had Clinical Evidence of Hypervolemia at Baseline Week 142 (N= 12)	3.8 kg Standard Deviation 8.7
Mean Change From Baseline in Body Weight by Visit for Those Participants Who Had Clinical Evidence of Hypervolemia at Baseline Week 154 (N= 11)	2.7 kg Standard Deviation 7.9
Mean Change From Baseline in Body Weight by Visit for Those Participants Who Had Clinical Evidence of Hypervolemia at Baseline Week 166 (N= 9)	2.9 kg Standard Deviation 9.4
Mean Change From Baseline in Body Weight by Visit for Those Participants Who Had Clinical Evidence of Hypervolemia at Baseline Week 178 (N= 7)	3.2 kg Standard Deviation 8.6
Mean Change From Baseline in Body Weight by Visit for Those Participants Who Had Clinical Evidence of Hypervolemia at Baseline Week 190 (N= 5)	-2.4 kg Standard Deviation 4.5

SECONDARY outcome

Timeframe: Baseline to Week 214

Population: The ITT dataset comprised of data from all enrolled participants who had observations at Baseline and at least one Post-Baseline visit were analyzed. In the last observation carried forward (LOCF) dataset, missing data were filled in using the participant's preceding non-missing value, except that Baseline value will not be carried forward.

The PCS assess the physical and mental dimensions of health-related quality of life. The PCS is equal to the sum of the items of endurance activities, strength activities, gross coordination activities, and fine coordination activities. The PCS is a computed score with weighted function based on the 12 questions from the 8 subscales (physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, mental health) of the SF-12v1 questionnaire per instructions by the scale's publisher. The scale ranges from 0 to 100 with 0 representing the lowest level of health and 100 indicating the highest level of health.

Outcome measures

Measure	Tolvaptan n=111 Participants Participants received 15 mg tolvaptan QD and were titrated from 15mg, 30mg, or 60mg of tolvaptan based on the participant's response in serum sodium concentration and clinical tolerance of study drug.
Mean Change From Baseline in SF-12 (Health Survey) Physical Component Summary (PCS) Day 14 (N= 102)	1.0 Units on a scale Standard Deviation 7.3
Mean Change From Baseline in SF-12 (Health Survey) Physical Component Summary (PCS) Day 31 (N= 106)	0.4 Units on a scale Standard Deviation 7.9
Mean Change From Baseline in SF-12 (Health Survey) Physical Component Summary (PCS) Week 10 (N= 106)	0.3 Units on a scale Standard Deviation 8.1
Mean Change From Baseline in SF-12 (Health Survey) Physical Component Summary (PCS) Week 18 (N= 106)	0.4 Units on a scale Standard Deviation 8.1
Mean Change From Baseline in SF-12 (Health Survey) Physical Component Summary (PCS) Week 26 (N= 106)	-0.9 Units on a scale Standard Deviation 9.7
Mean Change From Baseline in SF-12 (Health Survey) Physical Component Summary (PCS) Week 34 (N= 106)	-0.3 Units on a scale Standard Deviation 9.4
Mean Change From Baseline in SF-12 (Health Survey) Physical Component Summary (PCS) Week 42 (N= 106)	-1.1 Units on a scale Standard Deviation 9.4
Mean Change From Baseline in SF-12 (Health Survey) Physical Component Summary (PCS) Week 50 (N= 106)	-1.1 Units on a scale Standard Deviation 9.0
Mean Change From Baseline in SF-12 (Health Survey) Physical Component Summary (PCS) Week 58 (N= 106)	-0.9 Units on a scale Standard Deviation 9.0
Mean Change From Baseline in SF-12 (Health Survey) Physical Component Summary (PCS) Week 70 (N= 106)	-1.1 Units on a scale Standard Deviation 9.1
Mean Change From Baseline in SF-12 (Health Survey) Physical Component Summary (PCS) Week 82 (N= 106)	-0.9 Units on a scale Standard Deviation 8.9
Mean Change From Baseline in SF-12 (Health Survey) Physical Component Summary (PCS) Week 94 (N= 106)	-1.6 Units on a scale Standard Deviation 9.1
Mean Change From Baseline in SF-12 (Health Survey) Physical Component Summary (PCS) Week 106 (N= 106)	-1.7 Units on a scale Standard Deviation 8.4
Mean Change From Baseline in SF-12 (Health Survey) Physical Component Summary (PCS) Week 142 (N= 2)	-9.1 Units on a scale Standard Deviation 10.8
Mean Change From Baseline in SF-12 (Health Survey) Physical Component Summary (PCS) Week 166 (N= 2)	4.6 Units on a scale Standard Deviation 9.7
Mean Change From Baseline in SF-12 (Health Survey) Physical Component Summary (PCS) Week 178 (N= 2)	-11.3 Units on a scale Standard Deviation 2.5
Mean Change From Baseline in SF-12 (Health Survey) Physical Component Summary (PCS) Week 190 (N= 6)	-2.2 Units on a scale Standard Deviation 5.6
Mean Change From Baseline in SF-12 (Health Survey) Physical Component Summary (PCS) Week 202 (N= 1)	0.6 Units on a scale Standard Deviation NA Standard deviation (SD) is not calculated at Week 202 as there was only 1 participant.
Mean Change From Baseline in SF-12 (Health Survey) Physical Component Summary (PCS) Week 214 (N= 6)	4.0 Units on a scale Standard Deviation 9.2

SECONDARY outcome

Timeframe: Baseline to Week 214

Population: The ITT dataset comprised of data from all enrolled participants who had observations at Baseline and at least one Post-Baseline visit were analyzed. In the last observation carried forward (LOCF) dataset, missing data were filled in using the participant's preceding non-missing value, except that Baseline value will not be carried forward.

The MCS assess the physical and mental dimensions of health-related quality of life. The MCS is equal to the sum of the items of concentration activities, calculating activities, language activities, and memory activities. The MCS is a computed score with weighted function based on the 12 questions from the 8 subscales (physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, mental health) of the SF-12v1 questionnaire per instructions by the scale's publisher. The scale ranges from 0 to 100 with 0 representing the lowest level of health and 100 indicating the highest level of health.

Outcome measures

Measure	Tolvaptan n=103 Participants Participants received 15 mg tolvaptan QD and were titrated from 15mg, 30mg, or 60mg of tolvaptan based on the participant's response in serum sodium concentration and clinical tolerance of study drug.
Mean Change From Baseline in SF-12 (Health Survey) Mental Component Summary (MCS) Day 14 (N= 102)	-1.0 Units on a scale Standard Deviation 8.8
Mean Change From Baseline in SF-12 (Health Survey) Mental Component Summary (MCS) Day 31 (N= 106)	-1.0 Units on a scale Standard Deviation 9.6
Mean Change From Baseline in SF-12 (Health Survey) Mental Component Summary (MCS) Week 10 (N= 106)	-0.4 Units on a scale Standard Deviation 9.8
Mean Change From Baseline in SF-12 (Health Survey) Mental Component Summary (MCS) Week 18 (N= 106)	-2.0 Units on a scale Standard Deviation 8.8
Mean Change From Baseline in SF-12 (Health Survey) Mental Component Summary (MCS) Week 26 (N= 106)	-1.1 Units on a scale Standard Deviation 8.8
Mean Change From Baseline in SF-12 (Health Survey) Mental Component Summary (MCS) Week 34 (N= 106)	-2.7 Units on a scale Standard Deviation 9.4
Mean Change From Baseline in SF-12 (Health Survey) Mental Component Summary (MCS) Week 42 (N= 106)	-2.1 Units on a scale Standard Deviation 10.1
Mean Change From Baseline in SF-12 (Health Survey) Mental Component Summary (MCS) Week 50 (N= 106)	-1.9 Units on a scale Standard Deviation 10.4
Mean Change From Baseline in SF-12 (Health Survey) Mental Component Summary (MCS) Week 58 (N= 106)	-2.5 Units on a scale Standard Deviation 11.4
Mean Change From Baseline in SF-12 (Health Survey) Mental Component Summary (MCS) Week 70 (N= 106)	-2.6 Units on a scale Standard Deviation 10.7
Mean Change From Baseline in SF-12 (Health Survey) Mental Component Summary (MCS) Week 82 (N= 106)	-2.5 Units on a scale Standard Deviation 10.5
Mean Change From Baseline in SF-12 (Health Survey) Mental Component Summary (MCS) Week 94 (N= 106)	-2.6 Units on a scale Standard Deviation 10.5
Mean Change From Baseline in SF-12 (Health Survey) Mental Component Summary (MCS) Week 106 (N= 106)	-3.7 Units on a scale Standard Deviation 11.6
Mean Change From Baseline in SF-12 (Health Survey) Mental Component Summary (MCS) Week 142 (N= 2)	-11.2 Units on a scale Standard Deviation 27.6
Mean Change From Baseline in SF-12 (Health Survey) Mental Component Summary (MCS) Week 166 (N= 2)	5.0 Units on a scale Standard Deviation 13.6
Mean Change From Baseline in SF-12 (Health Survey) Mental Component Summary (MCS) Week 178 (N= 2)	0.4 Units on a scale Standard Deviation 4.5
Mean Change From Baseline in SF-12 (Health Survey) Mental Component Summary (MCS) Week 190 (N= 6)	-2.8 Units on a scale Standard Deviation 8.2
Mean Change From Baseline in SF-12 (Health Survey) Mental Component Summary (MCS) Week 202 (N= 1)	-0.8 Units on a scale Standard Deviation NA SD was not calculated at Week 202 as there was only 1 participant.
Mean Change From Baseline in SF-12 (Health Survey) Mental Component Summary (MCS) Week 214 (N= 6)	-0.5 Units on a scale Standard Deviation 7.8

SECONDARY outcome

Timeframe: Baseline to Week 214

Population: The Hyponatremia Disease-specific Survey PCS and MCS scores evaluated during the trial were variable with only nominal changes from baseline observed. The data were collected under 2 different datasets, so the number of participants in each dataset was reduced that limited analysis of this endpoint.

Analysis of individual items of Hyponatremia Disease-specific Survey was not conducted, because the analysis of Hyponatremia Disease-specific Survey was focused on the PCS and MCS summary scores since these 2 scores were developed. Subgroup analyses of Hyponatremia Disease-specific Survey were also not conducted.

Outcome measures

Outcome data not reported

Adverse Events

Tolvaptan

Serious events: 76 serious events

Other events: 86 other events

Deaths: 0 deaths

Serious adverse events

Measure	Tolvaptan n=111 participants at risk Participants received 15 mg tolvaptan QD and were titrated from 15mg, 30mg, or 60mg of tolvaptan based on the participant's response in serum sodium concentration and clinical tolerance of study drug.
Blood and lymphatic system disorders Anemia	3.6% 4/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Blood and lymphatic system disorders Spontaneous haematoma	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Cardiac disorders Acute coronary syndrome	1.8% 2/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Cardiac disorders Arrhythmia	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Cardiac disorders Atrial fibrillation	2.7% 3/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Cardiac disorders Atrial flutter	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Cardiac disorders Atrial tachycardia	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Cardiac disorders Bradycardia	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Cardiac disorders Cardiac arrest	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Cardiac disorders Cardiac failure	6.3% 7/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Cardiac disorders Cardiac failure congestive	6.3% 7/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Cardiac disorders Cardiac tamponade	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Cardiac disorders Cardio-respiratory arrest	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Cardiac disorders Coronary artery disease	2.7% 3/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Cardiac disorders Left ventricular failure	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Cardiac disorders Sick sinus syndrome	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Cardiac disorders Sinus tachycardia	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Cardiac disorders Tachycardia	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Cardiac disorders Ventricular tachycardia	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Ear and labyrinth disorders Vertigo	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Endocrine disorders Goitre	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Eye disorders Blindness	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Eye disorders Retinal detachment	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Eye disorders Retinal haemorrhage	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Eye disorders Retinoschisis	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Gastrointestinal disorders Abdominal hernia	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Gastrointestinal disorders Abdominal pain upper	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Gastrointestinal disorders Ascites	4.5% 5/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Gastrointestinal disorders Colitis ischaemic	1.8% 2/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Gastrointestinal disorders Diarrhoea	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Gastrointestinal disorders Diverticulum	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Gastrointestinal disorders Dysphagia	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Gastrointestinal disorders Gastritis	1.8% 2/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Gastrointestinal disorders Gastritis erosive	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Gastrointestinal disorders Gastrointestinal haemorrhage	4.5% 5/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Gastrointestinal disorders Haematemesis	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Gastrointestinal disorders Inguinal hernia	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Gastrointestinal disorders Intestinal obstruction	1.8% 2/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Gastrointestinal disorders Malaena	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Gastrointestinal disorders Nausea	1.8% 2/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Gastrointestinal disorders Oesophageal varices haemorrhage	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Gastrointestinal disorders Pancreatitis acute	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Gastrointestinal disorders Peritonitis	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Gastrointestinal disorders Rectal haemorrhage	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Gastrointestinal disorders Umbilical hernia	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Gastrointestinal disorders Umbilical hernia perforation	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Gastrointestinal disorders Volvulus	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Gastrointestinal disorders Vomiting	1.8% 2/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
General disorders Adverse drug reaction	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
General disorders Chest pain	4.5% 5/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
General disorders Gait disturbance	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
General disorders General physical health deterioration	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
General disorders Hernia	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
General disorders Multi-organ failure	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
General disorders Non-cardiac chest pain	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
General disorders Oedema peripheral	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
General disorders Ulcer haemorrhage	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Hepatobiliary disorders Cholecystitis acute	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Hepatobiliary disorders Cholelithiasis	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Hepatobiliary disorders Hepatic cirrhosis	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Hepatobiliary disorders Hepatorenal syndrome	1.8% 2/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Hepatobiliary disorders Portal hypertensive gastropathy	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Infections and infestations Bronchitis	1.8% 2/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Infections and infestations Catheter site infection	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Infections and infestations Cellulitis	1.8% 2/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Infections and infestations Clostridium difficile colitis	1.8% 2/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Infections and infestations Cystitis	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Infections and infestations Diabetic gangrene	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Infections and infestations Gastroenteritis	1.8% 2/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Infections and infestations Heliobacter gastritis	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Infections and infestations Infection	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Infections and infestations Influenza	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Infections and infestations Localised infection	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Infections and infestations Peritonitis bacterial	1.8% 2/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Infections and infestations Pneumonia	9.0% 10/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Infections and infestations Sepsis	1.8% 2/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Infections and infestations Sepsis syndrome	1.8% 2/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Infections and infestations Urinary tract infection	2.7% 3/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Infections and infestations Urosepsis	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Injury, poisoning and procedural complications Compression fracture	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Injury, poisoning and procedural complications Excoriation	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Injury, poisoning and procedural complications Fall	1.8% 2/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Injury, poisoning and procedural complications Hip fracture	2.7% 3/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Injury, poisoning and procedural complications Humerus fracture	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Injury, poisoning and procedural complications Lumbar vertebral fracture	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Injury, poisoning and procedural complications Procedural pain	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Injury, poisoning and procedural complications Rib fracture	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Injury, poisoning and procedural complications Skin laceration	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Injury, poisoning and procedural complications Spinal compression fracture	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Injury, poisoning and procedural complications Subdural haematoma	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Injury, poisoning and procedural complications Therapeutic agent toxicity	1.8% 2/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Injury, poisoning and procedural complications Ulna fracture	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Injury, poisoning and procedural complications Vascular graft occlusion	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Investigations Blood creatinine increased	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Investigations International normalised ratio increased	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Investigations Troponin increased	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Metabolism and nutrition disorders Dehydration	1.8% 2/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Metabolism and nutrition disorders Failure to thrive	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Metabolism and nutrition disorders Fluid overload	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Metabolism and nutrition disorders Hyperkalaemia	2.7% 3/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Metabolism and nutrition disorders Hypervolaemia	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Metabolism and nutrition disorders Hypocalcaemia	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Metabolism and nutrition disorders Hypoglycaemia	1.8% 2/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Metabolism and nutrition disorders Hypokalaemia	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Metabolism and nutrition disorders Hyponatraemia	9.0% 10/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Musculoskeletal and connective tissue disorders Back pain	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Musculoskeletal and connective tissue disorders Muscular weakness	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Musculoskeletal and connective tissue disorders Osteoarthritis	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Musculoskeletal and connective tissue disorders Osteonecrosis	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Musculoskeletal and connective tissue disorders Rhabdomyolysis	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Musculoskeletal and connective tissue disorders Rotator cuff syndrome	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bladder cancer	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colon cancer	1.8% 2/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung neoplasm malignant	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Non-Hodgkin's lymphoma unspecified histology aggressive refracto	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer	1.8% 2/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Nervous system disorders Altered state of consciousness	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Nervous system disorders Anoxic encephalopathy	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Nervous system disorders Ataxia	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Nervous system disorders Cerebral haemorrhage	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Nervous system disorders Cerebral ischaemia	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Nervous system disorders Cerebrovascular accident	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Nervous system disorders Convulsion	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Nervous system disorders Dysphasia	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Nervous system disorders Encephalopathy	4.5% 5/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Nervous system disorders Epilepsy	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Nervous system disorders Haemorrhagic cerebral infarction	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Nervous system disorders Hepatic encephalopathy	1.8% 2/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Nervous system disorders Hydrocephalus	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Nervous system disorders Polyneuropathy	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Nervous system disorders Reversible ischaemic neurological deficit	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Nervous system disorders Syncope	2.7% 3/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Nervous system disorders Transient ischaemic attack	1.8% 2/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Psychiatric disorders Alcoholism	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Psychiatric disorders Confusional state	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Psychiatric disorders Depression	2.7% 3/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Psychiatric disorders Mental status changes	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Psychiatric disorders Obsessive-compulsive disorder	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Psychiatric disorders Panic disorder	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Psychiatric disorders Psychotic disorder	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Renal and urinary disorders Bladder neck sclerosis	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Renal and urinary disorders Hypertonic bladder	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Renal and urinary disorders Renal failure	3.6% 4/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Renal and urinary disorders Renal failure acute	2.7% 3/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Renal and urinary disorders Renal impairment	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Respiratory, thoracic and mediastinal disorders Aspiration	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Respiratory, thoracic and mediastinal disorders Pneumonia aspiration	1.8% 2/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Respiratory, thoracic and mediastinal disorders Pulmonary oedema	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Respiratory, thoracic and mediastinal disorders Respiratory distress	1.8% 2/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Respiratory, thoracic and mediastinal disorders Respiratory failure	1.8% 2/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Vascular disorders Arteriosclerosis	1.8% 2/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Vascular disorders Hypertension	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Vascular disorders Hypotension	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Vascular disorders Lymphocele	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Vascular disorders Peripheral ischaemia	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Vascular disorders Peripheral vascular disorder	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Vascular disorders Temporal arteritis	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Vascular disorders Vascular insufficiency	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Vascular disorders Venous thrombosis limb	0.90% 1/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.

Other adverse events

Measure	Tolvaptan n=111 participants at risk Participants received 15 mg tolvaptan QD and were titrated from 15mg, 30mg, or 60mg of tolvaptan based on the participant's response in serum sodium concentration and clinical tolerance of study drug.
Blood and lymphatic system disorders Anaemia	14.4% 16/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Endocrine disorders Hypothyroidism	5.4% 6/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Gastrointestinal disorders Abdominal pain	6.3% 7/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Gastrointestinal disorders Ascites	9.9% 11/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Gastrointestinal disorders Constipation	7.2% 8/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Gastrointestinal disorders Diarrhoea	18.0% 20/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Gastrointestinal disorders Dyspepsia	5.4% 6/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Gastrointestinal disorders Nausea	16.2% 18/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Gastrointestinal disorders Vomiting	9.0% 10/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
General disorders Asthenia	5.4% 6/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
General disorders Chest pain	7.2% 8/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
General disorders Fatigue	13.5% 15/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
General disorders Oedema	5.4% 6/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
General disorders Oedema peripheral	22.5% 25/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
General disorders Pain	5.4% 6/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
General disorders Pyrexia	5.4% 6/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
General disorders Thirst	12.6% 14/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Infections and infestations Bronchitis	7.2% 8/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Infections and infestations Gastroenteritis	6.3% 7/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Infections and infestations Nasopharyngitis	6.3% 7/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Infections and infestations Upper respiratory tract infection	5.4% 6/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Infections and infestations Urinary tract infection	16.2% 18/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Injury, poisoning and procedural complications Contusion	7.2% 8/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Injury, poisoning and procedural complications Fall	5.4% 6/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Injury, poisoning and procedural complications Skin laceration	5.4% 6/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Metabolism and nutrition disorders Hypokalaemia	11.7% 13/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Metabolism and nutrition disorders Hyponatraemia	15.3% 17/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Musculoskeletal and connective tissue disorders Arthralgia	7.2% 8/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Musculoskeletal and connective tissue disorders Back pain	10.8% 12/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Musculoskeletal and connective tissue disorders Muscle spasms	5.4% 6/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	9.0% 10/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Nervous system disorders Dizziness	10.8% 12/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Nervous system disorders Headache	13.5% 15/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Nervous system disorders Lethargy	5.4% 6/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Psychiatric disorders Insomnia	8.1% 9/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Renal and urinary disorders Pollakiuria	10.8% 12/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Renal and urinary disorders Renal failure	6.3% 7/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Respiratory, thoracic and mediastinal disorders Cough	8.1% 9/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Respiratory, thoracic and mediastinal disorders Dyspnoea	9.9% 11/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Respiratory, thoracic and mediastinal disorders Dyspnoea exertional	6.3% 7/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Respiratory, thoracic and mediastinal disorders Epistaxis	5.4% 6/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Respiratory, thoracic and mediastinal disorders Nasal congestion	5.4% 6/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Skin and subcutaneous tissue disorders Ecchymosis	6.3% 7/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Vascular disorders Hypertension	6.3% 7/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.
Vascular disorders Hypotension	10.8% 12/111 • AEs are reported from the signing of the informed consent until the follow-up visit (+7 days) after the last dose of study drug as scheduled or as an early termination.

Additional Information

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