Hyponatremia, Dilutional Hyponatremia, Inappropriate ADH Syndrome
Conditions
Keywords
Hyponatremia, Dilutional Hyponatremia, Euvolemic Hyponatremia, Hypervolemic Hyponatremia, Fluid Restriction, Tolvaptan
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.
Interventions
DRUGtolvaptan
15 mg titrated to 30 mg then 60 mg once daily as oral tablet for up to 7 days based on response.
OTHERFluid 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
Sponsors
Otsuka Pharmaceutical Development & Commercialization, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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 |
| 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. |
| 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. |
| 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. |
| Percentage of Participants Requiring Rescue Therapy for Hyponatremia | 7 days | Percentage of participants requiring rescue therapy within first 7 days of treatment for hyponatremia. |
| 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. |
Countries
United States
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 66 |
| Placebo Placebo tablet with prescribed fluid restriction. After the initial dose, level of fluid restriction may be titrated based on serum sodium response. | 58 |
| Total | 124 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 3 |
| Overall Study | Participant met withdrawal criteria | 0 | 1 |
| Overall Study | Physician Decision | 6 | 6 |
| Overall Study | Withdrawal by Subject | 3 | 0 |
Baseline characteristics
| Characteristic | Tolvaptan 15-60 mg/Day | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 65.7 Years STANDARD_DEVIATION 15.8 | 67.7 Years STANDARD_DEVIATION 15.6 | 66.7 Years STANDARD_DEVIATION 15.7 |
| Sex: Female, Male Female | 29 Participants | 34 Participants | 63 Participants |
| Sex: Female, Male Male | 37 Participants | 24 Participants | 61 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 52 / 66 | 43 / 55 |
| serious Total, serious adverse events | 18 / 66 | 9 / 55 |
Outcome results
Primary
Length of Hospital Stay (LoS)
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
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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tolvaptan 15-60mg/Day | Length of Hospital Stay (LoS) | 3.5 Days |
| Placebo | Length of Hospital Stay (LoS) | 4.0 Days |
p-value: 0.9495Generalized Wilcoxon Test
Secondary
Change From Baseline in Serum Sodium Concentration (24 Hour Area Under the Curve [AUC]).
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
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 3 participants in the tolvaptan group and 1 participant in the placebo group.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Tolvaptan 15-60mg/Day | Change From Baseline in Serum Sodium Concentration (24 Hour Area Under the Curve [AUC]). | 3.90 mEq/L |
| Placebo | Change From Baseline in Serum Sodium Concentration (24 Hour Area Under the Curve [AUC]). | 0.13 mEq/L |
p-value: 0.001995% CI: [1.43, 6.11]ANCOVA
Secondary
Change From Baseline to 24 and 72 Hours Post Dose in CGI-S of Hyponatremia Symptoms.
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
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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Tolvaptan 15-60mg/Day | Change From Baseline to 24 and 72 Hours Post Dose in CGI-S of Hyponatremia Symptoms. | Baseline | 4.0 Units on a scale |
| Tolvaptan 15-60mg/Day | 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 |
| Tolvaptan 15-60mg/Day | 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 |
| Tolvaptan 15-60mg/Day | 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 |
| Tolvaptan 15-60mg/Day | 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 |
| Placebo | Change From Baseline to 24 and 72 Hours Post Dose in CGI-S of Hyponatremia Symptoms. | Change from baseline at 72 hours | -1.0 Units on a scale |
| Placebo | Change From Baseline to 24 and 72 Hours Post Dose in CGI-S of Hyponatremia Symptoms. | Baseline | 4.0 Units on a scale |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
Comparison: P value corresponds to 24 hours post-dose.p-value: 0.31595% CI: [-0.57, 0.19]ANCOVA
Comparison: P value corresponds to 72 hours post-dose.p-value: 0.538195% CI: [-0.57, 0.3]ANCOVA
Secondary
Change From Baseline to 48 Hour Post Dose in Clinical Global Impression-Severity (CGI-S) of Hyponatremia Symptoms.
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
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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Tolvaptan 15-60mg/Day | 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 |
| Tolvaptan 15-60mg/Day | 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 |
| Tolvaptan 15-60mg/Day | 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 |
| Placebo | 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 |
| Placebo | Change From Baseline to 48 Hour Post Dose in Clinical Global Impression-Severity (CGI-S) of Hyponatremia Symptoms. | 48 hours post dose | 3.0 Units on a scale |
| Placebo | 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 |
p-value: 0.14695% CI: [-0.7, 0.11]ANCOVA
Secondary
Change From Baseline to 48 Hours Post Dose in Clinical Global Impression - Improvement (CGI-I) Score of Hyponatremia Symptoms.
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
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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tolvaptan 15-60mg/Day | 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 |
| Placebo | 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 |
p-value: 0.270295% CI: [-0.73, 0.21]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Requiring Rescue Therapy for Hyponatremia
Percentage of participants requiring rescue therapy within first 7 days of treatment for hyponatremia.
Time frame: 7 days
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 3 participants in the placebo group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tolvaptan 15-60mg/Day | Percentage of Participants Requiring Rescue Therapy for Hyponatremia | 3.03 Percentage of participants |
| Placebo | Percentage of Participants Requiring Rescue Therapy for Hyponatremia | 9.09 Percentage of participants |
p-value: 0.156895% CI: [0.07, 1.65]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Clinical Global Impression-Improvement (CGI-I) Score Improved to a Score of 1 or 2.
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
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 2 participants in the tolvaptan group and 3 participants in the placebo group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tolvaptan 15-60mg/Day | Percentage of Participants With Clinical Global Impression-Improvement (CGI-I) Score Improved to a Score of 1 or 2. | 57.8 Percentage of participants |
| Placebo | Percentage of Participants With Clinical Global Impression-Improvement (CGI-I) Score Improved to a Score of 1 or 2. | 52.7 Percentage of participants |
p-value: 0.579595% CI: [0.79, 1.52]Cochran-Mantel-Haenszel
Secondary
Time to First 2-point Improvement in CGI-S Score.
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
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 1 participant in the tolvaptan group and 3 participants in the placebo group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tolvaptan 15-60mg/Day | Time to First 2-point Improvement in CGI-S Score. | 51 Hours |
| Placebo | Time to First 2-point Improvement in CGI-S Score. | 69 Hours |
p-value: 0.5128Generalized Wilcoxon Test