SALACIA: Effects of Tolvaptan vs Fluid Restriction in Hospitalized Subjects With Dilutional Hyponatremia

• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01227512
• Collaborator: (none)
• Enrollment: 124
• Locations: 56
• Arms: 2
• Duration (Months): 31
• Patients Per Site: 2.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to determine if hospitalized patients with symptomatic hyponatremia treated with tolvaptan are in the hospital for less time than patients treated with fluid restriction. The study will also test if tolvaptan is better than fluid restriction in treating the symptoms of hyponatremia in hospitalized patients.

Condition or Disease	Intervention/Treatment	Phase
Hyponatremia; Dilutional Hyponatremia; Inappropriate ADH Syndrome	Drug: tolvaptan; Other: Fluid Restriction	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 124 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Participant)
• Primary Purpose: Treatment
• Official Title: Phase 3b, Multicenter, Randomized, Single-blind, Parallel Group Trial of the Effects of Titrated Oral SAMSCA(r) (Tolvaptan) 15, 30, or 60 mg QD Compared to Placebo Plus Fluid Restriction on Length of Hospital Stay and Symptoms in Subjects Hospitalized With Dilutional Hyponatremia
• Study Start Date: Oct 1, 2010
• Actual Primary Completion Date: May 1, 2013
• Actual Study Completion Date: May 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tolvaptan 15-60mg Oral tablet without fluid restriction. After the initial dose, daily dose may be titrated based on response.	Drug: tolvaptan; 15 mg titrated to 30 mg then 60 mg once daily as oral tablet for up to 7 days based on response.; Other Names: SAMSCA OPC-41061 OPC-156
Active Comparator: Fluid Restriction Placebo tablet with prescribed fluid restriction. After the initial dose, level of fluid restriction may titrated based response.	Other: Fluid Restriction; Placebo tablet once daily with prescribed daily fluid intake of 1500 mL, then intensifying to 2 lower volumes of fluid intake for up to 7 days based on response. Since all particpants were blinded to treatment, titration to stricter fluid restriction followed the same algorithm as tolvaptan, increasing both the level of fluid restriction and increasing the placebo "dose"

Outcome Measures

Primary Outcome Measures

1. Length of Hospital Stay (LoS) [45 days]

   LoS was time to clinically ready to be hospital discharged (CRBD) from study treatment initiation, disregarding prolonged hospitalization due solely to social factors.

Secondary Outcome Measures

1. Change From Baseline to 48 Hour Post Dose in Clinical Global Impression-Severity (CGI-S) of Hyponatremia Symptoms. [Baseline to 48 hours post dose]

   Change from baseline in blinded rater assessed CGI-S at 48 hours post-first dose or at discharge/rescue therapy, if earlier was assessed. The CGI-S is a one-question rating scale which was as follows: "Considering your total clinical experience with hyponatremia symptoms in this particular population, how symptomatic is the patient at this time?" 0=not assessed; 1=normal, not at all symtpmatic; 2=borderline symptomatic; 3=mildly symptomatic; 4=moderately symptomatic; 5=markedly symptomatic; 6=severely symptomatic; 7=among the most severly symptomatic patients.

2. Change From Baseline to 24 and 72 Hours Post Dose in CGI-S of Hyponatremia Symptoms. [Baseline to 24 and 72 hours post dose]

   Change in CGI-S of hyponatremia symptoms from pretreatment baseline at 24 and 72 hours post-first dose, or at discharge/rescue therapy if earlier was assessed. The CGI-S is a one-question rating scale which was as follows: "Considering your total clinical experience with hyponatremia symptoms in this particular population, how symptomatic is the patient at this time?" 0=not assessed; 1=normal, not at all symtpmatic; 2=borderline symptomatic; 3=mildly symptomatic; 4=moderately symptomatic; 5=markedly symptomatic; 6=severely symptomatic; 7=among the most severly symptomatic patients.

3. Change From Baseline to 48 Hours Post Dose in Clinical Global Impression - Improvement (CGI-I) Score of Hyponatremia Symptoms. [Baseline to 48 hours post dose]

   Change in CGI-I score at 48 hours post-first dose or discharge/rescue therapy, if earlier was assessed. The CGI-I is a one-question rating scale where the participant is asked to rate total improvement whether or not, in their judgment, it is due entirely to trial treatment. Compared to his/her condition at admission to the trial, how much has he/she changed? 0=not assessed; 1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; 7=very much worse

4. Change From Baseline in Serum Sodium Concentration (24 Hour Area Under the Curve [AUC]). [0 to 72 hours]

   Average 24 hour AUC of serum sodium concentration change from baseline, from Day 1 Hour 0 up to 72 hours post-first dose was assessed. A serum sodium sample was drawn at pre-treament and 8, 24, 48, and 72 hours post-first dose. Serum sodium was also assessed between 36 and 72 hours after the last dose. Analysis of AUC was for daily average AUC, hence the units or AUC are mEq/L/24 hours.

5. Time to First 2-point Improvement in CGI-S Score. [Up to 72 hours]

   CGI-S data up to 72 hours were used to identify 2-point improvements. Please refer to outcome measure 2 for details on the scale. For the analysis of time to first 2-point improvement in CGI-S, CGI-S data up to Hour 72 were used to identify 2-point improvements. Data for participants who received rescue therapy were censored at the time of receiving rescue therapy. For participants who were discharged before Hour 72 without reaching 2-point improvement in CGI-S, data were censored at the time of discharge. Other participants who did not reach the 2-point improvement during the 72 hours also had their data censored at their last CGI-S observations within 72 hours.

6. Percentage of Participants With Clinical Global Impression-Improvement (CGI-I) Score Improved to a Score of 1 or 2. [48 hours post dose]

   Percentage of responders (defined as CGI-I score of 1 = very much improved or 2 = much improved) at 48 hours post-first dose, or at discharge/rescue therapy, if earlier. Participants given rescue therapy were given a score of 7.

7. Percentage of Participants Requiring Rescue Therapy for Hyponatremia [7 days]

   Percentage of participants requiring rescue therapy within first 7 days of treatment for hyponatremia.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Hyponatremia in clinically euvolemic or hypervolemic states, defined as serum sodium < 130 mEq/L prior to randomization

• Clinically significant symptoms of hyponatremia, defined as a CGI-S score between 3-6, inclusive

• Female subjects of child bearing potential who agree to remain abstinent or to practice double-barrier forms of birth control from screening through 30 days following first dose on IMP

Exclusion Criteria:

• Women who are pregnant or breast feeding, and females of childbearing potential who are not using acceptable contraceptive methods (such as barrier contraceptives or methods that result in a failure rate of less than 1%)

• Hyponatremia in hypovolemic states, defined as the presence of clinical and historical evidence of extracellular fluid volume depletion, including but not limited to skin turgor, orthostatic changes in blood pressure or heart rate, dry mucous membranes, or a response to IV saline challenge

• Subjects who are likely to require prolonged hospitalization for reasons other than hyponatremia, eg. new femoral fracture, surgeries requiring extended recovery

• Recent prior treatment for hyponatremia: hypertonic saline (including normal saline challenge) (within 8 hours of baseline) or urea, lithium, demeclocycline, conivaptan or tolvaptan (within 4 days of baseline). Includes any treatment, other than fluid restriction for the purpose of increasing serum sodium.

• Hyponatremia symptoms of a severity (eg, CGI = 7) such that they require immediate intervention with hypertonic saline; or are expected to require such therapy within 48 hours

• Causes of neurological symptoms which are attributable to psychological (psychosis), structural (dementia of the Alzheimer's type, stroke, transient ischemic attack, multi-infarct dementia) or other metabolic causes (eg. hyper- or hypo-: oxemia, glycemia, calcemia, ammonemia, etc)

• Acute and transient hyponatremia associated with head trauma or severe neurological injury (eg. stroke, subdural hematoma)or the use of recreational drugs.

• History of hyponatremia known to be due to severe, untreated hypothyroidism/adrenal insufficiency

• Subjects with psychogenic polydipsia

• Systolic arterial blood pressure < 90 mmHg at screening

• History of hypersensitivity and/or idiosyncratic reaction to benzazepine or benzazepine derivatives (such as benazepril), or tolvaptan

• History of drug or medication abuse within the 3 months prior to screening, or current alcohol abuse

• Uncontrolled diabetes mellitus defined as glucose > 300 mg/dL [16.7 mmol/L]

• Current urinary tract obstruction (eg, obstructive benign prostatic hypertrophy)

• Current condition of anuria

• Serum creatinine > 3.5 mg/dL at screening

• Terminally ill or moribund condition with little chance of short-term (eg, 30 day) survival

• Subjects whose hyponatremia is the result of any medication that can safely be withdrawn (examples of drugs often not withdrawn include: anticonvulsants [eg, carbamazepine] and antipsychotics [eg, haloperidol])

• Patients receiving DDAVP within 2 days of screening

• Patients with history of active variceal bleeding within the past 30 days, without prior approval from sponsor medical monitor

• Participation in another investigational drug trial within the past 30 days

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Otsuka Investigational Site	Birmingham	Alabama	United States	35216
2	Otsuka Investigational Site	Birmingham	Alabama	United States	35242
3	Otsuka Investigational Site	Mobile	Alabama	United States	36608
4	Otsuka Investigational Site	Azusa	California	United States	91702
5	Otsuka Investigational Site	Banning	California	United States	92220
6	Otsuka Investigational Site	Culver City	California	United States	90232
7	Otsuka Investigational Site	Fountain Valley	California	United States	92708
8	Otsuka Investigational Site	Los Angeles	California	United States	90025
9	Otsuka Investigational Site	Los Angeles	California	United States	90033
10	Otsuka Investigational Site	Northridge	California	United States	91324
11	Otuska Investigational Site	Orange	California	United States	92868
12	Otsuka Investigational Site	Yorba Linda	California	United States	92886
13	Otsuka Investigational Site	Denver	Colorado	United States	80210
14	Otsuka Investigational Site	Washington	District of Columbia	United States	20010
15	Otsuka Investigational Site	Jacksonville	Florida	United States	32207
16	Otsuka Investigational Site	Jacksonville	Florida	United States	32209
17	Otsuka Investigational Site	Jacksonville	Florida	United States	32216
18	Otsuka Investigational Site	Orlando	Florida	United States	32803
19	Otsuka Investigational Site	Port Charlotte	Florida	United States	33952
20	Otsuka Investigational Site	Savannah	Georgia	United States	31405
21	Otsuka Investigational Site	Elizabethtown	Kentucky	United States	42701
22	Otsuka Investigational Site	Baltimore	Maryland	United States	21215
23	Otsuka Investigational Site	Springfield	Massachusetts	United States	01107
24	Otsuka Investigational Site	Saginaw	Michigan	United States	48602
25	Otsuka Investigational Site	Southfield	Michigan	United States	48075
26	Otsuka Investigational Site	Minneapolis	Minnesota	United States	55455
27	Otsuka Investigational Site	Rochester	Minnesota	United States	55905
28	Otsuka Investigational Site	Jackson	Mississippi	United States	39216
29	Otsuka Investigational Site	St. Louis	Missouri	United States	63110
30	Otsuka Investigational Site	Grand Island	Nebraska	United States	68803
31	Otsuka Investigational Site	Omaha	Nebraska	United States	68131
32	Otsuka Investigational Site	Haddon Heights	New Jersey	United States	08035
33	Otsuka Investigational Site	Newark	New Jersey	United States	07103
34	Otsuka Investigational Site	Bronx	New York	United States	10461
35	Otsuka Investigational Site	Buffalo	New York	United States	14203
36	Otsuka Investigational Site	Buffalo	New York	United States	14215
37	Otsuka Investigational Site	Jamaica	New York	United States	11418
38	Otsuka Investigational Site	New York	New York	United States	10032
39	Otsuka Investigational Site	Cincinnati	Ohio	United States	45267
40	Otsuka Investigational Site	Cleveland	Ohio	United States	44195
41	Otsuka Investigational Site	Columbus	Ohio	United States	43212
42	Otsuka Investigational Site	Fairfield	Ohio	United States	45014
43	Otsuka Investigational Site	Toledo	Ohio	United States	43560
44	Otsuka Investigational Site	Oklahoma City	Oklahoma	United States	73120
45	Otsuka Investigational Site	Bethleham	Pennsylvania	United States	18017
46	Otsuka Investigational Site	Philadelphia	Pennsylvania	United States	19102
47	Otsuka Investigational Site	Philadelphia	Pennsylvania	United States	19140
48	Otsuka Investigational Site	West Reading	Pennsylvania	United States	19611
49	Otsuka Investigational Site	Providence	Rhode Island	United States	02903
50	Otsuka Investigational Site	Galveston	Texas	United States	77555
51	Otsuka Investigational Site	Houston	Texas	United States	77030
52	Otsuka Investigational Site	Mission	Texas	United States	78572
53	Otsuka Investigational Site	San Antonio	Texas	United States	78205
54	Otsuka Investigational Site	San Antonio	Texas	United States	78229
55	Otsuka Investigational Site	Fairfax	Virginia	United States	22030
56	Otsuka Investigational Site	Madison	Wisconsin	United States	53705

Sponsors and Collaborators

• Otsuka Pharmaceutical Development & Commercialization, Inc.

Investigators

• Study Director: Ann Dandurand, MD, Otsuka Pharmaceutical Development & Commercialization, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
• ClinicalTrials.gov Identifier: NCT01227512
• Other Study ID Numbers: 156-08-275
• First Posted: Oct 25, 2010
• Last Update Posted: Oct 30, 2014
• Last Verified: Oct 1, 2014

• Keywords provided by Otsuka Pharmaceutical Development & Commercialization, Inc.: Hyponatremia; Dilutional Hyponatremia; Euvolemic Hyponatremia; Hypervolemic Hyponatremia; Fluid Restriction; Tolvaptan
• Additional relevant MeSH terms: Inappropriate ADH Syndrome; Hyponatremia; Tolvaptan

Study Results

Participant Flow

Recruitment Details	A total of 191 participants were recruited at 81 study sites in the United States (US). A total of 124 participants were randomised to treatment.
Pre-assignment Detail	Participants randomized 1:1 to tolvaptan (15 mg/day,titrated to 30 mg/day or 60 mg/day) without fluid restriction or placebo with titrated fluid restriction (500 to 1500 mL/day). Stratified based on severity of baseline symptoms (3-4, or 5-6 on the Clinical Global Impression of Severity and study center. All partipants were blinded to treatment.

Arm/Group Title	Tolvaptan 15-60 mg/Day	Placebo
Arm/Group Description	Oral tablet without fluid restriction. After the initial dose, daily dose was to be titrated to 30 mg/day or 60 mg/day based on serum sodium response.	Placebo tablet with prescribed fluid restriction. After the initial dose, level of fluid restriction may be titrated based on serum sodium response.
Period Title: Overall Study
STARTED	66	58
COMPLETED	53	48
NOT COMPLETED	13	10

Baseline Characteristics

Arm/Group Title	Tolvaptan 15-60 mg/Day	Placebo	Total
Arm/Group Description	Oral tablet without fluid restriction. After the initial dose, daily dose was to be titrated to 30 mg/day or 60 mg/day based on serum sodium response.	Placebo tablet with prescribed fluid restriction. After the initial dose, level of fluid restriction may be titrated based on serum sodium response.	Total of all reporting groups
Overall Participants	66	58	124
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	65.7 (15.8)	67.7 (15.6)	66.7 (15.7)
Sex: Female, Male (Count of Participants)
Female	29 43.9%	34 58.6%	63 50.8%
Male	37 56.1%	24 41.4%	61 49.2%

Outcome Measures

1. Primary Outcome

Title	Length of Hospital Stay (LoS)
Description	LoS was time to clinically ready to be hospital discharged (CRBD) from study treatment initiation, disregarding prolonged hospitalization due solely to social factors.
Time Frame	45 days

Outcome Measure Data

Analysis Population Description

Analysis was performed on the modified intent-to-treat population (MITT) which included all randomized participants who received at least one dose of study drug regardless of any protocol violation.

Arm/Group Title	Tolvaptan 15-60mg/Day	Placebo
Arm/Group Description	Oral tablet without fluid restriction. After the initial dose, daily dose was to be titrated to 30 mg/day or 60 mg/day based on serum sodium response.	Placebo tablet with prescribed fluid restriction. After the initial dose, level of fluid restriction may be titrated based on serum sodium response.
Measure Participants	66	55
Median (95% Confidence Interval) [Days]	3.5	4.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan 15-60mg/Day, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9495
	Comments	The alpha level was set at 0.05
	Method	Generalized Wilcoxon Test
	Comments	Participants who used rescue therapy within first 7 days of treatment period were censored at time they started the rescue therapy.

2. Secondary Outcome

Title	Change From Baseline to 48 Hour Post Dose in Clinical Global Impression-Severity (CGI-S) of Hyponatremia Symptoms.
Description	Change from baseline in blinded rater assessed CGI-S at 48 hours post-first dose or at discharge/rescue therapy, if earlier was assessed. The CGI-S is a one-question rating scale which was as follows: "Considering your total clinical experience with hyponatremia symptoms in this particular population, how symptomatic is the patient at this time?" 0=not assessed; 1=normal, not at all symtpmatic; 2=borderline symptomatic; 3=mildly symptomatic; 4=moderately symptomatic; 5=markedly symptomatic; 6=severely symptomatic; 7=among the most severly symptomatic patients.
Time Frame	Baseline to 48 hours post dose

Outcome Measure Data

Analysis Population Description

Analysis was performed on the modified intent-to-treat population (MITT) which included all randomized participants who received at least one dose of study drug regardless of any protocol violation. Data were missing for one participant in the Tolvaptan group.

Arm/Group Title	Tolvaptan 15-60mg/Day	Placebo
Arm/Group Description	Oral tablet without fluid restriction. After the initial dose, daily dose was to be titrated to 30 mg/day or 60 mg/day based on serum sodium response.	Placebo tablet with prescribed fluid restriction. After the initial dose, level of fluid restriction be may titrated based on serum sodium response.
Measure Participants	65	55
Baseline	4.0	4.0
48 hours post dose	2.0	3.0
Change from baseline	-1.0	-1.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan 15-60mg/Day, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1460
	Comments	alpha level was set at 0.05. p-value was derived from an ANCOVA model with treatment and clinical center as factors and baseline value as covariate.
	Method	ANCOVA
	Comments	Includes factors of treatment, study center and covariate baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.30
	Confidence Interval	() 95%; -0.70 to 0.11
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline to 24 and 72 Hours Post Dose in CGI-S of Hyponatremia Symptoms.
Description	Change in CGI-S of hyponatremia symptoms from pretreatment baseline at 24 and 72 hours post-first dose, or at discharge/rescue therapy if earlier was assessed. The CGI-S is a one-question rating scale which was as follows: "Considering your total clinical experience with hyponatremia symptoms in this particular population, how symptomatic is the patient at this time?" 0=not assessed; 1=normal, not at all symtpmatic; 2=borderline symptomatic; 3=mildly symptomatic; 4=moderately symptomatic; 5=markedly symptomatic; 6=severely symptomatic; 7=among the most severly symptomatic patients.
Time Frame	Baseline to 24 and 72 hours post dose

Outcome Measure Data

Analysis Population Description

Analysis was performed on the modified intent-to-treat population (MITT) which included all randomized participants who received at least one dose of study drug regardless of any protocol violation. Data were missing for one participant in the Tolvaptan group.

Arm/Group Title	Tolvaptan 15-60mg/Day	Placebo
Arm/Group Description	Oral tablet without fluid restriction. After the initial dose, daily dose was to be titrated to 30 mg/day or 60 mg/day based on serum sodium response.	Placebo tablet with prescribed fluid restriction. After the initial dose, level of fluid restriction may be titrated based on serum sodium response.
Measure Participants	65	55
Baseline	4.0	4.0
24 hours post-dose	3.0	3.0
Change from baseline at 24 hours	-1.0	-1.0
72 hours post-dose	2.0	2.0
Change from baseline at 72 hours	-2.0	-1.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan 15-60mg/Day, Placebo
	Comments	P value corresponds to 24 hours post-dose.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3150
	Comments
	Method	ANCOVA
	Comments	P-value was derived from an ANCOVA model with treatment and clinical center as factors and baseline value as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.19
	Confidence Interval	() 95%; -0.57 to 0.19
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan 15-60mg/Day, Placebo
	Comments	P value corresponds to 72 hours post-dose.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5381
	Comments
	Method	ANCOVA
	Comments	P-value was derived from an ANCOVA model with treatment and clinical center as factors and baseline value as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.13
	Confidence Interval	() 95%; -0.57 to 0.30
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline to 48 Hours Post Dose in Clinical Global Impression - Improvement (CGI-I) Score of Hyponatremia Symptoms.
Description	Change in CGI-I score at 48 hours post-first dose or discharge/rescue therapy, if earlier was assessed. The CGI-I is a one-question rating scale where the participant is asked to rate total improvement whether or not, in their judgment, it is due entirely to trial treatment. Compared to his/her condition at admission to the trial, how much has he/she changed? 0=not assessed; 1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; 7=very much worse
Time Frame	Baseline to 48 hours post dose

Outcome Measure Data

Analysis Population Description

Analysis was performed on the modified intent-to-treat population (MITT) which included all randomized participants who received at least one dose of study drug regardless of any protocol violation. Data were not available for 2 participants in the tolvaptan group.

Arm/Group Title	Tolvaptan 15-60mg/Day	Placebo
Arm/Group Description	Oral tablet without fluid restriction. After the initial dose, daily dose was to be titrated to 30 mg/day or 60 mg/day based on serum sodium response.	Placebo tablet with prescribed fluid restriction. After the initial dose, level of fluid restriction may be titrated based on serum sodium response.
Measure Participants	64	55
Median (Full Range) [Units on a scale]	2.0	2.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan 15-60mg/Day, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2702
	Comments	P-value was derived from a Cochran-Mantel-Haenszel (CMH) row mean scores test.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.26
	Confidence Interval	() 95%; -0.73 to 0.21
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline in Serum Sodium Concentration (24 Hour Area Under the Curve [AUC]).
Description	Average 24 hour AUC of serum sodium concentration change from baseline, from Day 1 Hour 0 up to 72 hours post-first dose was assessed. A serum sodium sample was drawn at pre-treament and 8, 24, 48, and 72 hours post-first dose. Serum sodium was also assessed between 36 and 72 hours after the last dose. Analysis of AUC was for daily average AUC, hence the units or AUC are mEq/L/24 hours.
Time Frame	0 to 72 hours

Outcome Measure Data

Analysis Population Description

Analysis was performed on the modified intent-to-treat population (MITT) which included all randomized participants who received at least one dose of study drug regardless of any protocol violation. Data were missing for 3 participants in the tolvaptan group and 1 participant in the placebo group.

Arm/Group Title	Tolvaptan 15-60mg/Day	Placebo
Arm/Group Description	Oral tablet without fluid restriction. After the initial dose, daily dose was to be titrated to 30 mg/day or 60 mg/day based on serum sodium response.	Placebo tablet with prescribed fluid restriction. After the initial dose, level of fluid restriction may titrated based on serum sodium response.
Measure Participants	63	54
Least Squares Mean (Full Range) [mEq/L]	3.90	0.13

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan 15-60mg/Day, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0019
	Comments	P-value was derived from an ANCOVA model with treatment and clinical center as factors and baseline value as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.77
	Confidence Interval	() 95%; 1.43 to 6.11
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Time to First 2-point Improvement in CGI-S Score.
Description	CGI-S data up to 72 hours were used to identify 2-point improvements. Please refer to outcome measure 2 for details on the scale. For the analysis of time to first 2-point improvement in CGI-S, CGI-S data up to Hour 72 were used to identify 2-point improvements. Data for participants who received rescue therapy were censored at the time of receiving rescue therapy. For participants who were discharged before Hour 72 without reaching 2-point improvement in CGI-S, data were censored at the time of discharge. Other participants who did not reach the 2-point improvement during the 72 hours also had their data censored at their last CGI-S observations within 72 hours.
Time Frame	Up to 72 hours

Outcome Measure Data

Analysis Population Description

Analysis was performed on the modified intent-to-treat population (MITT) which included all randomized participants who received at least one dose of study drug regardless of any protocol violation. Data were missing for 1 participant in the tolvaptan group and 3 participants in the placebo group.

Arm/Group Title	Tolvaptan 15-60mg/Day	Placebo
Arm/Group Description	Oral tablet without fluid restriction. After the initial dose, daily dose was to be titrated to 30 mg/day or 60 mg/day based on serum sodium response.	Placebo tablet with prescribed fluid restriction. After the initial dose, level of fluid restriction may be titrated based on serum sodium response.
Measure Participants	65	55
Median (95% Confidence Interval) [Hours]	51	69

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan 15-60mg/Day, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5128
	Comments	p-value was derived from Generalized Wilcoxon test stratified by treatment. Participants who received rescue therapy were censored at the time of receiving rescue therapy.
	Method	Generalized Wilcoxon Test
	Comments

7. Secondary Outcome

Title	Percentage of Participants With Clinical Global Impression-Improvement (CGI-I) Score Improved to a Score of 1 or 2.
Description	Percentage of responders (defined as CGI-I score of 1 = very much improved or 2 = much improved) at 48 hours post-first dose, or at discharge/rescue therapy, if earlier. Participants given rescue therapy were given a score of 7.
Time Frame	48 hours post dose

Outcome Measure Data

Analysis Population Description

Analysis was performed on the modified intent-to-treat population (MITT) which included all randomized participants who received at least one dose of study drug regardless of any protocol violation. Data were missing for 2 participants in the tolvaptan group and 3 participants in the placebo group.

Arm/Group Title	Tolvaptan 15-60mg/Day	Placebo
Arm/Group Description	Oral tablet without fluid restriction. After the initial dose, daily dose was to be titrated to 30 mg/day or 60 mg/day based on serum sodium response.	Placebo tablet with prescribed fluid restriction. After the initial dose, level of fluid restriction may be titrated based on serum sodium response.
Measure Participants	64	55
Number [Percentage of participants]	57.8 87.6%	52.7 90.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan 15-60mg/Day, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5795
	Comments	P-value was derived using a CMH test stratified by hyponatremia symptoms severity.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Relative Risk
	Estimated Value	1.10
	Confidence Interval	() 95%; 0.79 to 1.52
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Percentage of Participants Requiring Rescue Therapy for Hyponatremia
Description	Percentage of participants requiring rescue therapy within first 7 days of treatment for hyponatremia.
Time Frame	7 days

Outcome Measure Data

Analysis Population Description

Analysis was performed on the modified intent-to-treat population (MITT) which included all randomized participants who received at least one dose of study drug regardless of any protocol violation. Data were missing for 3 participants in the placebo group.

Arm/Group Title	Tolvaptan 15-60mg/Day	Placebo
Arm/Group Description	Oral tablet without fluid restriction. After the initial dose, daily dose was to be titrated to 30 mg/day or 60 mg/day based on serum sodium response.	Placebo tablet with prescribed fluid restriction. After the initial dose, level of fluid restriction may be titrated based on serum sodium response.
Measure Participants	66	55
Number [Percentage of participants]	3.03 4.6%	9.09 15.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan 15-60mg/Day, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1568
	Comments	p-value was derived using a CMH test stratified by hyponatremia symptoms severity.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Relative Risk
	Estimated Value	0.33
	Confidence Interval	() 95%; 0.07 to 1.65
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Adverse events were recorded from the time the Informed Consent Form was signed up to 45 days after study drug administration.
Adverse Event Reporting Description	The same event may appear as both an adverse event (AE) and a serious AE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Arm/Group Title	Tolvaptan 15-60 mg/Day		Placebo
Arm/Group Description	Oral tablet without fluid restriction. After the initial dose, daily dose was to be titrated to 30 mg/day or 60 mg/day based on serum sodium response.		Placebo tablet with prescribed fluid restriction. After the initial dose, level of fluid restriction may be titrated based on serum sodium response.
All Cause Mortality
	Tolvaptan 15-60 mg/Day		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Tolvaptan 15-60 mg/Day		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/66 (27.3%)		9/55 (16.4%)
Cardiac disorders
Acute myocardial infarction	1/66 (1.5%)		0/55 (0%)
Cardiac failure acute	1/66 (1.5%)		0/55 (0%)
Cardiac failure	1/66 (1.5%)		0/55 (0%)
Right ventricular failure	1/66 (1.5%)		0/55 (0%)
Gastrointestinal disorders
Diabetic gastroparesis	1/66 (1.5%)		0/55 (0%)
Intestinal obstruction	0/66 (0%)		1/55 (1.8%)
Lower gastrointestinal haemorrhage	1/66 (1.5%)		0/55 (0%)
Upper gastrointestinal haemorrhage	0/66 (0%)		1/55 (1.8%)
Hepatobiliary disorders
Cirrhosis alcoholic	1/66 (1.5%)		0/55 (0%)
Hepatic failure	1/66 (1.5%)		0/55 (0%)
Infections and infestations
Enterococcal infection	1/66 (1.5%)		0/55 (0%)
Pneumonia	2/66 (3%)		0/55 (0%)
Sepsis	1/66 (1.5%)		0/55 (0%)
Septic shock	2/66 (3%)		0/55 (0%)
Staphylococcal sepsis	0/66 (0%)		1/55 (1.8%)
Tuberculosis of central nervous system	1/66 (1.5%)		0/55 (0%)
Injury, poisoning and procedural complications
Femoral neck fracture	0/66 (0%)		1/55 (1.8%)
Metabolism and nutrition disorders
Hyponatraemia	2/66 (3%)		0/55 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung cancer metastatic	0/66 (0%)		1/55 (1.8%)
Metastatic malignant melanoma	1/66 (1.5%)		0/55 (0%)
Small cell lung cancer extensive stage	0/66 (0%)		1/55 (1.8%)
Psychiatric disorders
Confusional state	1/66 (1.5%)		0/55 (0%)
Renal and urinary disorders
Renal failure acute	3/66 (4.5%)		1/55 (1.8%)
Respiratory, thoracic and mediastinal disorders
Asthma	1/66 (1.5%)		0/55 (0%)
Respiratory failure	1/66 (1.5%)		0/55 (0%)
Surgical and medical procedures
Rapid correction of hyponatraemia	2/66 (3%)		0/55 (0%)
Vascular disorders
Deep vein thrombosis	0/66 (0%)		1/55 (1.8%)
Hypertension	0/66 (0%)		1/55 (1.8%)
Other (Not Including Serious) Adverse Events
	Tolvaptan 15-60 mg/Day		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	52/66 (78.8%)		43/55 (78.2%)
Gastrointestinal disorders
Abdominal distension	4/66 (6.1%)		0/55 (0%)
Abdominal pain	3/66 (4.5%)		3/55 (5.5%)
Constipation	10/66 (15.2%)		6/55 (10.9%)
Diarrhoea	3/66 (4.5%)		5/55 (9.1%)
Nausea	5/66 (7.6%)		3/55 (5.5%)
General disorders
Oedema peripheral	4/66 (6.1%)		4/55 (7.3%)
Pyrexia	3/66 (4.5%)		3/55 (5.5%)
Investigations
Heart rate increased	4/66 (6.1%)		3/55 (5.5%)
Metabolism and nutrition disorders
Hyperkalaemia	3/66 (4.5%)		3/55 (5.5%)
Hypokalaemia	5/66 (7.6%)		4/55 (7.3%)
Musculoskeletal and connective tissue disorders
Musculoskeletal pain	0/66 (0%)		3/55 (5.5%)
Pain in extremity	1/66 (1.5%)		3/55 (5.5%)
Nervous system disorders
Headache	4/66 (6.1%)		3/55 (5.5%)
Psychiatric disorders
Insomnia	3/66 (4.5%)		5/55 (9.1%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	4/66 (6.1%)		2/55 (3.6%)
Vascular disorders
Hypotension	9/66 (13.6%)		5/55 (9.1%)

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.