Trial Outcomes & Findings for Effects of Tolvaptan vs Fluid Restriction in Hospitalized Subjects With Dilutional Hyponatremia (NCT NCT01227512)

Last Updated: 2014-10-30

Results Overview

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

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

124 participants

Primary outcome timeframe

45 days

Results posted on

2014-10-30

Participant Flow

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.

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.

Participant milestones

Participant milestones
Measure	Tolvaptan 15-60 mg/Day 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 Placebo tablet with prescribed fluid restriction. After the initial dose, level of fluid restriction may be titrated based on serum sodium response.
Overall Study STARTED	66	58
Overall Study COMPLETED	53	48
Overall Study NOT COMPLETED	13	10

Reasons for withdrawal

Reasons for withdrawal
Measure	Tolvaptan 15-60 mg/Day 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 Placebo tablet with prescribed fluid restriction. After the initial dose, level of fluid restriction may be titrated based on serum sodium response.
Overall Study Physician Decision	6	6
Overall Study Adverse Event	4	3
Overall Study Withdrawal by Subject	3	0
Overall Study Participant met withdrawal criteria	0	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Tolvaptan 15-60 mg/Day n=66 Participants 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 n=58 Participants Placebo tablet with prescribed fluid restriction. After the initial dose, level of fluid restriction may be titrated based on serum sodium response.	Total n=124 Participants Total of all reporting groups
Age, Continuous	65.7 Years STANDARD_DEVIATION 15.8 • n=5 Participants	67.7 Years STANDARD_DEVIATION 15.6 • n=7 Participants	66.7 Years STANDARD_DEVIATION 15.7 • n=5 Participants
Sex: Female, Male Female	29 Participants n=5 Participants	34 Participants n=7 Participants	63 Participants n=5 Participants
Sex: Female, Male Male	37 Participants n=5 Participants	24 Participants n=7 Participants	61 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Tolvaptan 15-60mg/Day n=66 Participants 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 n=55 Participants Placebo tablet with prescribed fluid restriction. After the initial dose, level of fluid restriction may be titrated based on serum sodium response.
Length of Hospital Stay (LoS)	3.5 Days Interval 3.0 to 4.5	4.0 Days Interval 3.5 to 5.0

SECONDARY outcome

Timeframe: Baseline to 48 hours post dose

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Tolvaptan 15-60mg/Day n=65 Participants 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 n=55 Participants Placebo tablet with prescribed fluid restriction. After the initial dose, level of fluid restriction may be titrated based on serum sodium response.
Change From Baseline to 48 Hour Post Dose in Clinical Global Impression-Severity (CGI-S) of Hyponatremia Symptoms. Baseline	4.0 Units on a scale Interval 2.0 to 6.0	4.0 Units on a scale Interval 3.0 to 6.0
Change From Baseline to 48 Hour Post Dose in Clinical Global Impression-Severity (CGI-S) of Hyponatremia Symptoms. 48 hours post dose	2.0 Units on a scale Interval 1.0 to 6.0	3.0 Units on a scale Interval 1.0 to 7.0
Change From Baseline to 48 Hour Post Dose in Clinical Global Impression-Severity (CGI-S) of Hyponatremia Symptoms. Change from baseline	-1.0 Units on a scale Interval -3.0 to 3.0	-1.0 Units on a scale Interval -3.0 to 3.0

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Tolvaptan 15-60mg/Day n=65 Participants 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 n=55 Participants Placebo tablet with prescribed fluid restriction. After the initial dose, level of fluid restriction may be titrated based on serum sodium response.
Change From Baseline to 24 and 72 Hours Post Dose in CGI-S of Hyponatremia Symptoms. Baseline	4.0 Units on a scale Interval 2.0 to 6.0	4.0 Units on a scale Interval 3.0 to 6.0
Change From Baseline to 24 and 72 Hours Post Dose in CGI-S of Hyponatremia Symptoms. 24 hours post-dose	3.0 Units on a scale Interval 1.0 to 6.0	3.0 Units on a scale Interval 1.0 to 7.0
Change From Baseline to 24 and 72 Hours Post Dose in CGI-S of Hyponatremia Symptoms. 72 hours post-dose	2.0 Units on a scale Interval 1.0 to 6.0	2.0 Units on a scale Interval 1.0 to 7.0
Change From Baseline to 24 and 72 Hours Post Dose in CGI-S of Hyponatremia Symptoms. Change from baseline at 72 hours	-2.0 Units on a scale Interval -4.0 to 3.0	-1.0 Units on a scale Interval -4.0 to 4.0
Change From Baseline to 24 and 72 Hours Post Dose in CGI-S of Hyponatremia Symptoms. Change from baseline at 24 hours	-1.0 Units on a scale Interval -3.0 to 3.0	-1.0 Units on a scale Interval -3.0 to 2.0

SECONDARY outcome

Timeframe: Baseline to 48 hours post dose

Population: 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.

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

Outcome measures

Outcome measures
Measure	Tolvaptan 15-60mg/Day n=64 Participants 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 n=55 Participants Placebo tablet with prescribed fluid restriction. After the initial dose, level of fluid restriction may be titrated based on serum sodium response.
Change From Baseline to 48 Hours Post Dose in Clinical Global Impression - Improvement (CGI-I) Score of Hyponatremia Symptoms.	2.0 Units on a scale Interval 1.0 to 7.0	2.0 Units on a scale Interval 1.0 to 7.0

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Tolvaptan 15-60mg/Day n=63 Participants 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 n=54 Participants Placebo tablet with prescribed fluid restriction. After the initial dose, level of fluid restriction may be titrated based on serum sodium response.
Change From Baseline in Serum Sodium Concentration (24 Hour Area Under the Curve [AUC]).	3.90 mEq/L Interval -26.9 to 13.04	0.13 mEq/L Interval -20.6 to 11.76

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Tolvaptan 15-60mg/Day n=65 Participants 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 n=55 Participants Placebo tablet with prescribed fluid restriction. After the initial dose, level of fluid restriction may be titrated based on serum sodium response.
Time to First 2-point Improvement in CGI-S Score.	51 Hours Interval 49.0 to 72.0	69 Hours Interval 49.0 to 73.0

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Tolvaptan 15-60mg/Day n=64 Participants 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 n=55 Participants Placebo tablet with prescribed fluid restriction. After the initial dose, level of fluid restriction may be titrated based on serum sodium response.
Percentage of Participants With Clinical Global Impression-Improvement (CGI-I) Score Improved to a Score of 1 or 2.	57.8 Percentage of participants	52.7 Percentage of participants

SECONDARY outcome

Timeframe: 7 days

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

Outcome measures

Outcome measures
Measure	Tolvaptan 15-60mg/Day n=66 Participants 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 n=55 Participants Placebo tablet with prescribed fluid restriction. After the initial dose, level of fluid restriction may be titrated based on serum sodium response.
Percentage of Participants Requiring Rescue Therapy for Hyponatremia	3.03 Percentage of participants	9.09 Percentage of participants

Adverse Events

Tolvaptan 15-60 mg/Day

Serious events: 18 serious events

Other events: 52 other events

Deaths: 0 deaths

Placebo

Serious events: 9 serious events

Other events: 43 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Global Medical Affairs

Otsuka Pharmaceutical Development and Commercialization, Inc.

Phone: 800 562-3974

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Tolvaptan 15-60 mg/Day n=66 participants at risk 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 n=55 participants at risk Placebo tablet with prescribed fluid restriction. After the initial dose, level of fluid restriction may be titrated based on serum sodium response.
Gastrointestinal disorders Abdominal distension	6.1% 4/66 • Adverse events were recorded from the time the Informed Consent Form was signed up to 45 days after study drug administration. 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.	0.00% 0/55 • Adverse events were recorded from the time the Informed Consent Form was signed up to 45 days after study drug administration. 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.
Gastrointestinal disorders Abdominal pain	4.5% 3/66 • Adverse events were recorded from the time the Informed Consent Form was signed up to 45 days after study drug administration. 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.	5.5% 3/55 • Adverse events were recorded from the time the Informed Consent Form was signed up to 45 days after study drug administration. 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.
Gastrointestinal disorders Constipation	15.2% 10/66 • Adverse events were recorded from the time the Informed Consent Form was signed up to 45 days after study drug administration. 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.	10.9% 6/55 • Adverse events were recorded from the time the Informed Consent Form was signed up to 45 days after study drug administration. 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.
Gastrointestinal disorders Diarrhoea	4.5% 3/66 • Adverse events were recorded from the time the Informed Consent Form was signed up to 45 days after study drug administration. 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.	9.1% 5/55 • Adverse events were recorded from the time the Informed Consent Form was signed up to 45 days after study drug administration. 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.
Gastrointestinal disorders Nausea	7.6% 5/66 • Adverse events were recorded from the time the Informed Consent Form was signed up to 45 days after study drug administration. 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.	5.5% 3/55 • Adverse events were recorded from the time the Informed Consent Form was signed up to 45 days after study drug administration. 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.
General disorders Oedema peripheral	6.1% 4/66 • Adverse events were recorded from the time the Informed Consent Form was signed up to 45 days after study drug administration. 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.	7.3% 4/55 • Adverse events were recorded from the time the Informed Consent Form was signed up to 45 days after study drug administration. 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.
General disorders Pyrexia	4.5% 3/66 • Adverse events were recorded from the time the Informed Consent Form was signed up to 45 days after study drug administration. 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.	5.5% 3/55 • Adverse events were recorded from the time the Informed Consent Form was signed up to 45 days after study drug administration. 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.
Investigations Heart rate increased	6.1% 4/66 • Adverse events were recorded from the time the Informed Consent Form was signed up to 45 days after study drug administration. 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.	5.5% 3/55 • Adverse events were recorded from the time the Informed Consent Form was signed up to 45 days after study drug administration. 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.
Metabolism and nutrition disorders Hyperkalaemia	4.5% 3/66 • Adverse events were recorded from the time the Informed Consent Form was signed up to 45 days after study drug administration. 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.	5.5% 3/55 • Adverse events were recorded from the time the Informed Consent Form was signed up to 45 days after study drug administration. 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.
Metabolism and nutrition disorders Hypokalaemia	7.6% 5/66 • Adverse events were recorded from the time the Informed Consent Form was signed up to 45 days after study drug administration. 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.	7.3% 4/55 • Adverse events were recorded from the time the Informed Consent Form was signed up to 45 days after study drug administration. 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.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	0.00% 0/66 • Adverse events were recorded from the time the Informed Consent Form was signed up to 45 days after study drug administration. 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.	5.5% 3/55 • Adverse events were recorded from the time the Informed Consent Form was signed up to 45 days after study drug administration. 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.
Musculoskeletal and connective tissue disorders Pain in extremity	1.5% 1/66 • Adverse events were recorded from the time the Informed Consent Form was signed up to 45 days after study drug administration. 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.	5.5% 3/55 • Adverse events were recorded from the time the Informed Consent Form was signed up to 45 days after study drug administration. 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.
Nervous system disorders Headache	6.1% 4/66 • Adverse events were recorded from the time the Informed Consent Form was signed up to 45 days after study drug administration. 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.	5.5% 3/55 • Adverse events were recorded from the time the Informed Consent Form was signed up to 45 days after study drug administration. 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.
Psychiatric disorders Insomnia	4.5% 3/66 • Adverse events were recorded from the time the Informed Consent Form was signed up to 45 days after study drug administration. 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.	9.1% 5/55 • Adverse events were recorded from the time the Informed Consent Form was signed up to 45 days after study drug administration. 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.
Respiratory, thoracic and mediastinal disorders Dyspnoea	6.1% 4/66 • Adverse events were recorded from the time the Informed Consent Form was signed up to 45 days after study drug administration. 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.	3.6% 2/55 • Adverse events were recorded from the time the Informed Consent Form was signed up to 45 days after study drug administration. 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.
Vascular disorders Hypotension	13.6% 9/66 • Adverse events were recorded from the time the Informed Consent Form was signed up to 45 days after study drug administration. 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.	9.1% 5/55 • Adverse events were recorded from the time the Informed Consent Form was signed up to 45 days after study drug administration. 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.