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

• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02449044
• Collaborator: (none)
• Enrollment: 111
• Arm: 1
• Duration (Months): 65

Study Details

Study Description

Brief Summary

This study will assess the safety of long-term tolvaptan use in patients previously enrolled in shorter-term Phase 3 studies and gather information on the natural history of hyponatremia in the context of tolvaptan therapy and underlying disease states.

Condition or Disease	Intervention/Treatment	Phase
Hyponatremia	Drug: Tolvaptan	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 111 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: International, Multicenter, Study of One-year, Open-label, Titrated Oral Tolvaptan Tablet Administration in Patients With Chronic Hyponatremia: Extension to Studies 156-02-235 and 156-03-238 to Assess One-year Safety
• Study Start Date: May 1, 2004
• Actual Primary Completion Date: Oct 1, 2009
• Actual Study Completion Date: Oct 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tolvaptan Enrolled subjects began treatment with 15 mg tolvaptan QD. A titration between target doses of 15 mg, 30 mg, or 60 mg of trial medication was based on the subject's change in serum sodium concentration and clinical tolerance of the trial medication.	Drug: Tolvaptan; Once Daily

Outcome Measures

Primary Outcome Measures

1. Participants With Adverse Events (AEs) [Baseline to Post-Week 214 follow-up visit]

   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.

2. Participants With Laboratory Values Abnormalities Reported as TEAEs [Baseline to Post-Week 214 follow-up visit]

   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.

3. Participants With Electrocardiogram (ECG) Related Abnormalities Reported as TEAEs [Baseline to Post-Week 214 follow-up visit]

   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.

4. Participants With Vital Signs Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs) [Baseline to Post-Week 214 follow-up visit]

   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.

5. Participants With Body Weight Abnormalities Reported as TEAEs [Baseline to Post-Week 214 follow-up visit]

   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.

Secondary Outcome Measures

1. Mean Change From Baseline in Serum Sodium Measurements [Baseline of parent trial to Week 214]

   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.

2. Change From Baseline in Percentage of Participants With Severe Hyponatremia [Baseline to Week 214]

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

3. Change From Baseline in Percentage of Participants With Mild Hyponatremia [Baseline to Week 214]

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

4. Change From Baseline in Percentage of Participants With Normal Sodium Levels [Baseline to Week 214]

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

5. Percentage of Participants Requiring Prescription of Fluid Restriction [Baseline to Post-Week 214 follow-up visit]

   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.

6. Number of Participants Requiring Prescription of Hypertonic Saline [Baseline to Post-Week 214 follow-up visit]

   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.

7. Percentage of Participants Requiring Prescription of Other Medicines [Baseline to Post-Week 214 follow-up visit]

   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.

8. Mean Change From Baseline in Body Weight by Visit for Those Participants Who Had Clinical Evidence of Hypervolemia at Baseline [Baseline to Week 214]

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

9. Mean Change From Baseline in SF-12 (Health Survey) Physical Component Summary (PCS) [Baseline to Week 214]

   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.

10. Mean Change From Baseline in SF-12 (Health Survey) Mental Component Summary (MCS) [Baseline to Week 214]

    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.

11. Change From Baseline in the Hyponatremia Disease-specific Survey [Baseline to Week 214]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Age greater than or equal to 18 years.

2. Ability to provide informed consent or assent.

3. Prior successful participation in a tolvaptan hyponatremia trial termination with evidence of continued need or desire for therapy.

Exclusion Criteria:

• A current medical condition where long-term treatment with an aquaretic agent may present an undue risk to the patient.

• Hyponatremia which is acute, reversible, artifactual or due to conditions not associated with vasopressin excess or likely to respond to aquaretic therapy.

• Hyponatremia due to reversible medical condition or therapy

• Conditions associated with an independent imminent risk of morbidity and mortality

• Conditions which confound the assessment of endpoints.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Otsuka Pharmaceutical Development & Commercialization, Inc.

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
• ClinicalTrials.gov Identifier: NCT02449044
• Other Study ID Numbers: 156-03-244
• First Posted: May 20, 2015
• Last Update Posted: Jan 21, 2016
• Last Verified: Dec 1, 2015

• Keywords provided by Otsuka Pharmaceutical Development & Commercialization, Inc.: Hyponatremia
• Additional relevant MeSH terms: Hyponatremia; Tolvaptan

Study Results

Participant Flow

Recruitment Details	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.
Pre-assignment Detail	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.

Arm/Group Title	Tolvaptan
Arm/Group Description	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.
Period Title: Overall Study
STARTED	111
COMPLETED	47
NOT COMPLETED	64

Baseline Characteristics

Arm/Group Title	Tolvaptan
Arm/Group Description	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 Participants	111
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	64.6 (15.0)
Sex: Female, Male (Count of Participants)
Female	56 50.5%
Male	55 49.5%

Outcome Measures

1. Primary Outcome

Title	Participants With Adverse Events (AEs)
Description	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.
Time Frame	Baseline to Post-Week 214 follow-up visit

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tolvaptan
Arm/Group Description	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.
Measure Participants	111
Participants with TEAEs	105 94.6%
Participants with serious TEAEs	76 68.5%
Participants with severe TEAEs	73 65.8%
Participants discontinued IMP due to TEAE	19 17.1%
Participants discontinued IMP due to TEAE/death	28 25.2%
Deaths	19 17.1%

2. Primary Outcome

Title	Participants With Laboratory Values Abnormalities Reported as TEAEs
Description	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.
Time Frame	Baseline to Post-Week 214 follow-up visit

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tolvaptan
Arm/Group Description	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.
Measure Participants	111
Serum Chemistry-Blood creatinine increased	4 3.6%
Serum Chemistry-Blood potassium increased	4 3.6%
Serum Chemistry-Blood glucose increased	3 2.7%
Serum Chemistry-Blood potassium decreased	3 2.7%
SerumChemistry-Aspartate aminotransferaseincreased	2 1.8%
Serum Chemistry-Blood cholesterol increased	3 2.7%
Serum Chemistry-Blood sodium increased	2 1.8%
Serum Chemistry-Hepatic enzyme increased	2 1.8%
Serum Chemistry-Oxygen saturation decreased	2 1.8%
Serum Chemistry-Hyperglycaemia	5 4.5%
Serum Chemistry-Hyperkalaemia	7 6.3%
Serum Chemistry-Hyperlipidaemia	4 3.6%
Serum Chemistry-Hypernatraemia	4 3.6%
Serum Chemistry-Hyperuricaemia	3 2.7%
Serum Chemistry-Hypoglycaemia	5 4.5%
Serum Chemistry-Hypokalaemia	14 12.6%
Serum Chemistry-Hypomagnesaemia	3 2.7%
Serum Chemistry-Hypoatraemia	25 22.5%
Hematology-Anemia	20 18%
Hematology-Thrombocytopenia	2 1.8%
Hematology-International normalized ratioincreased	4 3.6%
Hematology-White blood cell count increased	2 1.8%

3. Primary Outcome

Title	Participants With Electrocardiogram (ECG) Related Abnormalities Reported as TEAEs
Description	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.
Time Frame	Baseline to Post-Week 214 follow-up visit

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tolvaptan
Arm/Group Description	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.
Measure Participants	111
Atrial fibrillation	6 5.4%
Tachycardia	4 3.6%
Atrial tachycardia	3 2.7%
First degree atrioventricular block	2 1.8%
Bradycardia	2 1.8%
Sinus tachycardia	2 1.8%
Ventricular tachycardia	2 1.8%
Left bundle branch block	1 0.9%
Tachyarrhythmia	1 0.9%
Ventricular arrhythmia	1 0.9%
Atrial flutter	1 0.9%
ECG ST segment depression	1 0.9%
Arrhythmia	1 0.9%

4. Primary Outcome

Title	Participants With Vital Signs Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs)
Description	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.
Time Frame	Baseline to Post-Week 214 follow-up visit

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tolvaptan
Arm/Group Description	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.
Measure Participants	111
Hypotension	13 11.7%
Hypertension	8 7.2%
Pyrexia	6 5.4%
Increased body temperature	3 2.7%
Palpitations	2 1.8%
Increased central venous pressure	2 1.8%
Increased venous pressure	1 0.9%
Orthostatic hypotension	1 0.9%
Hypertensive crisis	1 0.9%
Decreased orthostatic blood pressure	1 0.9%
Increased weight	5 4.5%
Decreased weight	1 0.9%

5. Primary Outcome

Title	Participants With Body Weight Abnormalities Reported as TEAEs
Description	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.
Time Frame	Baseline to Post-Week 214 follow-up visit

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tolvaptan
Arm/Group Description	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.
Measure Participants	111
Increased weight	5 4.5%
Decreased weight	1 0.9%

6. Secondary Outcome

Title	Mean Change From Baseline in Serum Sodium Measurements
Description	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.
Time Frame	Baseline of parent trial to Week 214

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tolvaptan
Arm/Group Description	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.
Measure Participants	111
Day 1 post-dose (N= 99)	2.2 (3.3)
Day 14 (N= 110)	5.2 (5.5)
Day 31 (N= 110)	5.0 (4.8)
Week 10 (N= 110)	5.0 (5.1)
Week 18 (N= 110)	4.6 (5.4)
Week 26 (N= 110)	4.2 (5.7)
Week 34 (N= 110)	4.7 (5.9)
Week 42 (N= 110)	5.2 (5.6)
Week 50 (N= 110)	5.0 (5.9)
Week 58 (N= 110)	5.0 (5.9)
Week 70 (N= 110)	4.8 (5.8)
Week 82 (N= 110)	4.8 (5.7)
Week 94 (N= 110)	5.1 (5.8)
Week 106 (N= 110)	5.0 (6.0)
Week 118 (N= 110)	4.8 (5.9)
Week 130 (N= 110)	4.9 (6.0)
Week 142 (N= 110)	5.2 (5.9)
Week 154 (N= 110)	5.2 (5.9)
Week 166 (N= 110)	4.9 (5.8)
Week 178 (N= 110)	4.8 (5.9)
Week 190 (N= 110)	5.1 (6.1)
Week 202 (N= 110)	5.0 (5.9)
Week 214 (N= 110)	5.0 (5.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	This was the p-value for analysis at Day 1.
	Method	Student's t-test
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	This was the p-value for analysis at Day 14.
	Method	Student's t-test
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	This was the p-value for analysis at Day 31.
	Method	Student's t-test
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	This was the p-value for analysis at Week 10.
	Method	Student's t-test
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	This was the p-value for analysis at Week 18.
	Method	Student's t-test
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	This was the p-value for analysis at Week 26.
	Method	Student's t-test
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	This was the p-value for analysis at Week 34.
	Method	Student's t-test
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	This was the p-value for analysis at Week 42.
	Method	Student's t-test
	Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	This was the p-value for analysis at Week 50.
	Method	Student's t-test
	Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	This was the p-value for analysis at Week 58.
	Method	Student's t-test
	Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	This was the p-value for analysis at Week 70.
	Method	Student's t-test
	Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	This was the p-value for analysis at Week 82.
	Method	Student's t-test
	Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	This was the p-value for analysis at Week 94.
	Method	Student's t-test
	Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	This was the p-value for analysis at Week 106.
	Method	Student's t-test
	Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	This was the p-value for analysis at Week 118.
	Method	Student's t-test
	Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	This was the p-value for analysis at Week 130.
	Method	Student's t-test
	Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	This was the p-value for analysis at Week 142.
	Method	Student's t-test
	Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	This was the p-value for analysis at Week 154.
	Method	Student's t-test
	Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	This was the p-value for analysis at Week 166.
	Method	Student's t-test
	Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	This was the p-value for analysis at Week 178.
	Method	Student's t-test
	Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	This was the p-value for analysis at Week 190.
	Method	Student's t-test
	Comments

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	This was the p-value for analysis at Week 202.
	Method	Student's t-test
	Comments

Statistical Analysis 23

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	This was the p-value for analysis at Week 214.
	Method	Student's t-test
	Comments

7. Secondary Outcome

Title	Change From Baseline in Percentage of Participants With Severe Hyponatremia
Description	Percentage of participants with varying degrees of hyponatremia ("severe" <130, "mild" 130-135, "normal" >135 mEq/L) at Baseline and each study visit.
Time Frame	Baseline to Week 214

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tolvaptan
Arm/Group Description	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.
Measure Participants	111
Day 1 post-dose (N=99)	20.2 (3.0) 18.2%
Day 31 (N=110)	9.1 (5.1) 8.2%
Week 10 (N=110)	11.8 (5.0) 10.6%
Week 18 (N=110)	13.6 (4.0) 12.3%
Week 26 (N=110)	16.4 (4.6) 14.8%
Week 34 (N=110)	14.5 (5.6) 13.1%
Week 42 (N=110)	12.7 (4.1) 11.4%
Week 50 (N=110)	10.9 (4.5) 9.8%
Week 58 (N=110)	13.6 (5.1) 12.3%
Week 70 (N=110)	12.7 (4.6) 11.4%
Week 82 (N=110)	10.9 (4.1) 9.8%
Week 94 (N=110)	10.9 (4.8) 9.8%
Week 106 (N=110)	12.7 (4.7) 11.4%
Week 118 (N=110)	12.7 (4.4) 11.4%
Week 130 (N=110)	11.8 (4.7) 10.6%
Week 142 (N=110)	11.8 (4.5) 10.6%
Week 154 (N=110)	11.8 (4.4) 10.6%
Week 166 (N=110)	11.8 (4.5) 10.6%
Week 178 (N=110)	11.8 (4.5) 10.6%
Week 190 (N=110)	11.8 (4.7) 10.6%
Week 202 (N=110)	11.8 (4.6) 10.6%
Week 214 (N=110)	11.8 (4.6) 10.6%

8. Secondary Outcome

Title	Change From Baseline in Percentage of Participants With Mild Hyponatremia
Description	Percentage of participants with varying degrees of hyponatremia ("severe" <130, "mild" 130-135, "normal" >135 mEq/L) at Baseline and each study visit.
Time Frame	Baseline to Week 214

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tolvaptan
Arm/Group Description	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.
Measure Participants	111
Day 1 post-dose (N=99)	53.5 48.2%
Day 31 (N=110)	33.6 30.3%
Week 10 (N=110)	28.2 25.4%
Week 18 (N=110)	33.6 30.3%
Week 26 (N=110)	30.9 27.8%
Week 34 (N=110)	26.4 23.8%
Week 42 (N=110)	26.4 23.8%
Week 50 (N=110)	31.8 28.6%
Week 58 (N=110)	26.4 23.8%
Week 70 (N=110)	30.9 27.8%
Week 82 (N=110)	31.8 28.6%
Week 94 (N=110)	28.2 25.4%
Week 106 (N=110)	27.3 24.6%
Week 118 (N=110)	28.2 25.4%
Week 130 (N=110)	29.1 26.2%
Week 142 (N=110)	25.5 23%
Week 154 (N=110)	25.5 23%
Week 166 (N=110)	30.9 27.8%
Week 178 (N=110)	30.9 27.8%
Week 190 (N=110)	30.9 27.8%
Week 202 (N=110)	30.9 27.8%
Week 214 (N=110)	30.9 27.8%

9. Secondary Outcome

Title	Change From Baseline in Percentage of Participants With Normal Sodium Levels
Description	Percentage of participants with varying degrees of hyponatremia ("severe" <130, "mild" 130-135, "normal" >135 mEq/L) at Baseline and each study visit.
Time Frame	Baseline to Week 214

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tolvaptan
Arm/Group Description	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.
Measure Participants	111
Day 1 post-dose (N=99)	26.3 23.7%
Day 31 (N=110)	57.3 51.6%
Week 10 (N=110)	60.0 54.1%
Week 18 (N=110)	52.7 47.5%
Week 26 (N=110)	52.7 47.5%
Week 34 (N=110)	59.1 53.2%
Week 42 (N=110)	60.9 54.9%
Week 50 (N=110)	57.3 51.6%
Week 58 (N=110)	60.0 54.1%
Week 70 (N=110)	56.4 50.8%
Week 82 (N=110)	57.3 51.6%
Week 94 (N=110)	60.9 54.9%
Week 106 (N=110)	60.0 54.1%
Week 118 (N=110)	59.1 53.2%
Week 130 (N=110)	59.1 53.2%
Week 142 (N=110)	62.7 56.5%
Week 154 (N=110)	62.7 56.5%
Week 166 (N=110)	57.3 51.6%
Week 178 (N=110)	57.3 51.6%
Week 190 (N=110)	57.3 51.6%
Week 202 (N=110)	58.2 52.4%
Week 214 (N=110)	57.3 51.6%

10. Secondary Outcome

Title	Percentage of Participants Requiring Prescription of Fluid Restriction
Description	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.
Time Frame	Baseline to Post-Week 214 follow-up visit

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tolvaptan
Arm/Group Description	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.
Measure Participants	111
Mild Hyponatremia (N=76)	14.47 13%
Severe Hyponatremia (N=35)	5.71 5.1%

11. Secondary Outcome

Title	Number of Participants Requiring Prescription of Hypertonic Saline
Description	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.
Time Frame	Baseline to Post-Week 214 follow-up visit

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tolvaptan
Arm/Group Description	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.
Measure Participants	111
Number [participants]	2 1.8%

12. Secondary Outcome

Title	Percentage of Participants Requiring Prescription of Other Medicines
Description	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.
Time Frame	Baseline to Post-Week 214 follow-up visit

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tolvaptan
Arm/Group Description	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.
Measure Participants	111
Number [percentage of participants]	0 0%

13. Secondary Outcome

Title	Mean Change From Baseline in Body Weight by Visit for Those Participants Who Had Clinical Evidence of Hypervolemia at Baseline
Description	Body weight at each visit (assessed only for those with clinical evidence of hypervolemia at Baseline) and was summarized using descriptive statistics.
Time Frame	Baseline to Week 214

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tolvaptan
Arm/Group Description	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.
Measure Participants	111
Day 31 (N= 26)	-0.5 (4.6)
Week 10 (N= 32)	-1.1 (3.7)
Week 18 (N= 27)	0.2 (3.0)
Week 26 (N= 27)	0.4 (5.4)
Week 34 (N= 26)	0.5 (4.0)
Week 42 (N= 24)	0.3 (4.6)
Week 50 (N= 22)	1.0 (4.7)
Week 58 (N= 22)	1.7 (4.5)
Week 70 (N= 18)	1.7 (5.2)
Week 82 (N= 18)	2.0 (7.0)
Week 94 (N= 18)	3.0 (8.0)
Week 106 (N= 15)	1.4 (8.0)
Week 118 (N= 13)	2.2 (8.1)
Week 130 (N= 13)	3.0 (9.0)
Week 142 (N= 12)	3.8 (8.7)
Week 154 (N= 11)	2.7 (7.9)
Week 166 (N= 9)	2.9 (9.4)
Week 178 (N= 7)	3.2 (8.6)
Week 190 (N= 5)	-2.4 (4.5)
Week 202 (N= 2)	-7.1 (0.4)
Week 214 (N= 2)	-8.5 (1.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Day 31
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4922
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 10
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1054
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 18
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7656
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 26
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7084
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 34
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5138
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 42
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7175
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 50
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3540
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 58
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0852
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 70
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1923
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 82
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2335
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 94
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1346
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 106
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5237
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 118
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3476
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 130
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2488
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 142
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1598
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 154
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2820
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 166
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3743
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 178
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3600
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 190
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3101
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 202
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0269
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 214
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0944
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

14. Secondary Outcome

Title	Mean Change From Baseline in SF-12 (Health Survey) Physical Component Summary (PCS)
Description	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.
Time Frame	Baseline to Week 214

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tolvaptan
Arm/Group Description	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.
Measure Participants	111
Day 14 (N= 102)	1.0 (7.3)
Day 31 (N= 106)	0.4 (7.9)
Week 10 (N= 106)	0.3 (8.1)
Week 18 (N= 106)	0.4 (8.1)
Week 26 (N= 106)	-0.9 (9.7)
Week 34 (N= 106)	-0.3 (9.4)
Week 42 (N= 106)	-1.1 (9.4)
Week 50 (N= 106)	-1.1 (9.0)
Week 58 (N= 106)	-0.9 (9.0)
Week 70 (N= 106)	-1.1 (9.1)
Week 82 (N= 106)	-0.9 (8.9)
Week 94 (N= 106)	-1.6 (9.1)
Week 106 (N= 106)	-1.7 (8.4)
Week 142 (N= 2)	-9.1 (10.8)
Week 166 (N= 2)	4.6 (9.7)
Week 178 (N= 2)	-11.3 (2.5)
Week 190 (N= 6)	-2.2 (5.6)
Week 202 (N= 1)	0.6 (NA)
Week 214 (N= 6)	4.0 (9.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Day 14
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1739
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student t-test
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Day 31
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6095
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 10
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6902
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 18
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6340
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 26
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3210
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 34
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7787
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 42
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2198
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 50
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1926
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 58
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3109
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 70
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2269
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 82
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2749
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 94
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0702
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 106
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0412
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 142
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4448
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 166
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6233
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 178
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1001
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 190
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3739
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 214
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3334
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

15. Secondary Outcome

Title	Mean Change From Baseline in SF-12 (Health Survey) Mental Component Summary (MCS)
Description	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.
Time Frame	Baseline to Week 214

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tolvaptan
Arm/Group Description	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.
Measure Participants	103
Day 14 (N= 102)	-1.0 (8.8)
Day 31 (N= 106)	-1.0 (9.6)
Week 10 (N= 106)	-0.4 (9.8)
Week 18 (N= 106)	-2.0 (8.8)
Week 26 (N= 106)	-1.1 (8.8)
Week 34 (N= 106)	-2.7 (9.4)
Week 42 (N= 106)	-2.1 (10.1)
Week 50 (N= 106)	-1.9 (10.4)
Week 58 (N= 106)	-2.5 (11.4)
Week 70 (N= 106)	-2.6 (10.7)
Week 82 (N= 106)	-2.5 (10.5)
Week 94 (N= 106)	-2.6 (10.5)
Week 106 (N= 106)	-3.7 (11.6)
Week 142 (N= 2)	-11.2 (27.6)
Week 166 (N= 2)	5.0 (13.6)
Week 178 (N= 2)	0.4 (4.5)
Week 190 (N= 6)	-2.8 (8.2)
Week 202 (N= 1)	-0.8 (NA)
Week 214 (N= 6)	-0.5 (7.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Day 14
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2575
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student t-test
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Day 31
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2715
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 10
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6860
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 18
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0224
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 26
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1871
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 34
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0039
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 42
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0325
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 50
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0631
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 58
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0277
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 70
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0128
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 82
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0164
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 94
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0119
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 106
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0013
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 142
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6691
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 166
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6923
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 178
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9292
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 190
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4401
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan
	Comments	Statistical analysis at Week 214
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3609
	Comments	Descriptive use only, no statistical adjustments for multiplicity were planned.
	Method	Student's t-test
	Comments

16. Secondary Outcome

Title	Change From Baseline in the Hyponatremia Disease-specific Survey
Description	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.
Time Frame	Baseline to Week 214

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tolvaptan
Arm/Group Description	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.
Measure Participants	0

Adverse Events

Time Frame	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.
Arm/Group Title	Tolvaptan
Arm/Group Description	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.
All Cause Mortality
	Tolvaptan
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Tolvaptan
	Affected / at Risk (%)	# Events
Total	76/111 (68.5%)
Blood and lymphatic system disorders
Anemia	4/111 (3.6%)
Spontaneous haematoma	1/111 (0.9%)
Cardiac disorders
Acute coronary syndrome	2/111 (1.8%)
Arrhythmia	1/111 (0.9%)
Atrial fibrillation	3/111 (2.7%)
Atrial flutter	1/111 (0.9%)
Atrial tachycardia	1/111 (0.9%)
Bradycardia	1/111 (0.9%)
Cardiac arrest	1/111 (0.9%)
Cardiac failure	7/111 (6.3%)
Cardiac failure congestive	7/111 (6.3%)
Cardiac tamponade	1/111 (0.9%)
Cardio-respiratory arrest	1/111 (0.9%)
Coronary artery disease	3/111 (2.7%)
Left ventricular failure	1/111 (0.9%)
Sick sinus syndrome	1/111 (0.9%)
Sinus tachycardia	1/111 (0.9%)
Tachycardia	1/111 (0.9%)
Ventricular tachycardia	1/111 (0.9%)
Ear and labyrinth disorders
Vertigo	1/111 (0.9%)
Endocrine disorders
Goitre	1/111 (0.9%)
Eye disorders
Blindness	1/111 (0.9%)
Retinal detachment	1/111 (0.9%)
Retinal haemorrhage	1/111 (0.9%)
Retinoschisis	1/111 (0.9%)
Gastrointestinal disorders
Abdominal hernia	1/111 (0.9%)
Abdominal pain upper	1/111 (0.9%)
Ascites	5/111 (4.5%)
Colitis ischaemic	2/111 (1.8%)
Diarrhoea	1/111 (0.9%)
Diverticulum	1/111 (0.9%)
Dysphagia	1/111 (0.9%)
Gastritis	2/111 (1.8%)
Gastritis erosive	1/111 (0.9%)
Gastrointestinal haemorrhage	5/111 (4.5%)
Haematemesis	1/111 (0.9%)
Inguinal hernia	1/111 (0.9%)
Intestinal obstruction	2/111 (1.8%)
Malaena	1/111 (0.9%)
Nausea	2/111 (1.8%)
Oesophageal varices haemorrhage	1/111 (0.9%)
Pancreatitis acute	1/111 (0.9%)
Peritonitis	1/111 (0.9%)
Rectal haemorrhage	1/111 (0.9%)
Umbilical hernia	1/111 (0.9%)
Umbilical hernia perforation	1/111 (0.9%)
Volvulus	1/111 (0.9%)
Vomiting	2/111 (1.8%)
General disorders
Adverse drug reaction	1/111 (0.9%)
Chest pain	5/111 (4.5%)
Gait disturbance	1/111 (0.9%)
General physical health deterioration	1/111 (0.9%)
Hernia	1/111 (0.9%)
Multi-organ failure	1/111 (0.9%)
Non-cardiac chest pain	1/111 (0.9%)
Oedema peripheral	1/111 (0.9%)
Ulcer haemorrhage	1/111 (0.9%)
Hepatobiliary disorders
Cholecystitis acute	1/111 (0.9%)
Cholelithiasis	1/111 (0.9%)
Hepatic cirrhosis	1/111 (0.9%)
Hepatorenal syndrome	2/111 (1.8%)
Portal hypertensive gastropathy	1/111 (0.9%)
Infections and infestations
Bronchitis	2/111 (1.8%)
Catheter site infection	1/111 (0.9%)
Cellulitis	2/111 (1.8%)
Clostridium difficile colitis	2/111 (1.8%)
Cystitis	1/111 (0.9%)
Diabetic gangrene	1/111 (0.9%)
Gastroenteritis	2/111 (1.8%)
Heliobacter gastritis	1/111 (0.9%)
Infection	1/111 (0.9%)
Influenza	1/111 (0.9%)
Localised infection	1/111 (0.9%)
Peritonitis bacterial	2/111 (1.8%)
Pneumonia	10/111 (9%)
Sepsis	2/111 (1.8%)
Sepsis syndrome	2/111 (1.8%)
Urinary tract infection	3/111 (2.7%)
Urosepsis	1/111 (0.9%)
Injury, poisoning and procedural complications
Compression fracture	1/111 (0.9%)
Excoriation	1/111 (0.9%)
Fall	2/111 (1.8%)
Hip fracture	3/111 (2.7%)
Humerus fracture	1/111 (0.9%)
Lumbar vertebral fracture	1/111 (0.9%)
Procedural pain	1/111 (0.9%)
Rib fracture	1/111 (0.9%)
Skin laceration	1/111 (0.9%)
Spinal compression fracture	1/111 (0.9%)
Subdural haematoma	1/111 (0.9%)
Therapeutic agent toxicity	2/111 (1.8%)
Ulna fracture	1/111 (0.9%)
Vascular graft occlusion	1/111 (0.9%)
Investigations
Blood creatinine increased	1/111 (0.9%)
International normalised ratio increased	1/111 (0.9%)
Troponin increased	1/111 (0.9%)
Metabolism and nutrition disorders
Dehydration	2/111 (1.8%)
Failure to thrive	1/111 (0.9%)
Fluid overload	1/111 (0.9%)
Hyperkalaemia	3/111 (2.7%)
Hypervolaemia	1/111 (0.9%)
Hypocalcaemia	1/111 (0.9%)
Hypoglycaemia	2/111 (1.8%)
Hypokalaemia	1/111 (0.9%)
Hyponatraemia	10/111 (9%)
Musculoskeletal and connective tissue disorders
Back pain	1/111 (0.9%)
Muscular weakness	1/111 (0.9%)
Osteoarthritis	1/111 (0.9%)
Osteonecrosis	1/111 (0.9%)
Rhabdomyolysis	1/111 (0.9%)
Rotator cuff syndrome	1/111 (0.9%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder cancer	1/111 (0.9%)
Colon cancer	2/111 (1.8%)
Lung neoplasm malignant	1/111 (0.9%)
Non-Hodgkin's lymphoma unspecified histology aggressive refracto	1/111 (0.9%)
Prostate cancer	2/111 (1.8%)
Nervous system disorders
Altered state of consciousness	1/111 (0.9%)
Anoxic encephalopathy	1/111 (0.9%)
Ataxia	1/111 (0.9%)
Cerebral haemorrhage	1/111 (0.9%)
Cerebral ischaemia	1/111 (0.9%)
Cerebrovascular accident	1/111 (0.9%)
Convulsion	1/111 (0.9%)
Dysphasia	1/111 (0.9%)
Encephalopathy	5/111 (4.5%)
Epilepsy	1/111 (0.9%)
Haemorrhagic cerebral infarction	1/111 (0.9%)
Hepatic encephalopathy	2/111 (1.8%)
Hydrocephalus	1/111 (0.9%)
Polyneuropathy	1/111 (0.9%)
Reversible ischaemic neurological deficit	1/111 (0.9%)
Syncope	3/111 (2.7%)
Transient ischaemic attack	2/111 (1.8%)
Psychiatric disorders
Alcoholism	1/111 (0.9%)
Confusional state	1/111 (0.9%)
Depression	3/111 (2.7%)
Mental status changes	1/111 (0.9%)
Obsessive-compulsive disorder	1/111 (0.9%)
Panic disorder	1/111 (0.9%)
Psychotic disorder	1/111 (0.9%)
Renal and urinary disorders
Bladder neck sclerosis	1/111 (0.9%)
Hypertonic bladder	1/111 (0.9%)
Renal failure	4/111 (3.6%)
Renal failure acute	3/111 (2.7%)
Renal impairment	1/111 (0.9%)
Respiratory, thoracic and mediastinal disorders
Aspiration	1/111 (0.9%)
Chronic obstructive pulmonary disease	1/111 (0.9%)
Pneumonia aspiration	2/111 (1.8%)
Pulmonary oedema	1/111 (0.9%)
Respiratory distress	2/111 (1.8%)
Respiratory failure	2/111 (1.8%)
Vascular disorders
Arteriosclerosis	2/111 (1.8%)
Hypertension	1/111 (0.9%)
Hypotension	1/111 (0.9%)
Lymphocele	1/111 (0.9%)
Peripheral ischaemia	1/111 (0.9%)
Peripheral vascular disorder	1/111 (0.9%)
Temporal arteritis	1/111 (0.9%)
Vascular insufficiency	1/111 (0.9%)
Venous thrombosis limb	1/111 (0.9%)
Other (Not Including Serious) Adverse Events
	Tolvaptan
	Affected / at Risk (%)	# Events
Total	86/111 (77.5%)
Blood and lymphatic system disorders
Anaemia	16/111 (14.4%)
Endocrine disorders
Hypothyroidism	6/111 (5.4%)
Gastrointestinal disorders
Abdominal pain	7/111 (6.3%)
Ascites	11/111 (9.9%)
Constipation	8/111 (7.2%)
Diarrhoea	20/111 (18%)
Dyspepsia	6/111 (5.4%)
Nausea	18/111 (16.2%)
Vomiting	10/111 (9%)
General disorders
Asthenia	6/111 (5.4%)
Chest pain	8/111 (7.2%)
Fatigue	15/111 (13.5%)
Oedema	6/111 (5.4%)
Oedema peripheral	25/111 (22.5%)
Pain	6/111 (5.4%)
Pyrexia	6/111 (5.4%)
Thirst	14/111 (12.6%)
Infections and infestations
Bronchitis	8/111 (7.2%)
Gastroenteritis	7/111 (6.3%)
Nasopharyngitis	7/111 (6.3%)
Upper respiratory tract infection	6/111 (5.4%)
Urinary tract infection	18/111 (16.2%)
Injury, poisoning and procedural complications
Contusion	8/111 (7.2%)
Fall	6/111 (5.4%)
Skin laceration	6/111 (5.4%)
Metabolism and nutrition disorders
Hypokalaemia	13/111 (11.7%)
Hyponatraemia	17/111 (15.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	8/111 (7.2%)
Back pain	12/111 (10.8%)
Muscle spasms	6/111 (5.4%)
Musculoskeletal pain	10/111 (9%)
Nervous system disorders
Dizziness	12/111 (10.8%)
Headache	15/111 (13.5%)
Lethargy	6/111 (5.4%)
Psychiatric disorders
Insomnia	9/111 (8.1%)
Renal and urinary disorders
Pollakiuria	12/111 (10.8%)
Renal failure	7/111 (6.3%)
Respiratory, thoracic and mediastinal disorders
Cough	9/111 (8.1%)
Dyspnoea	11/111 (9.9%)
Dyspnoea exertional	7/111 (6.3%)
Epistaxis	6/111 (5.4%)
Nasal congestion	6/111 (5.4%)
Skin and subcutaneous tissue disorders
Ecchymosis	7/111 (6.3%)
Vascular disorders
Hypertension	7/111 (6.3%)
Hypotension	12/111 (10.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.