Hyponatremia
Conditions
Keywords
Hyponatremia
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.
Interventions
DRUGTolvaptan
Once Daily
Sponsors
Otsuka Pharmaceutical Development & Commercialization, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| Tolvaptan Participants received 15 mg tolvaptan QD and were titrated from 15mg, 30mg, or 60mg of tolvaptan based on the participant's response in serum sodium concentration and clinical tolerance of study drug. | 111 |
| Total | 111 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 30 |
| Overall Study | Lost to Follow-up | 2 |
| Overall Study | Met Withdrawal Criteria | 7 |
| Overall Study | Physician Decision | 9 |
| Overall Study | Sponsor Discontinued Trial | 3 |
| Overall Study | Withdrawal by Subject | 13 |
Baseline characteristics
| Characteristic | Tolvaptan |
|---|---|
| Age, Continuous | 64.6 Years STANDARD_DEVIATION 15 |
| Sex: Female, Male Female | 56 Participants |
| Sex: Female, Male Male | 55 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 86 / 111 |
| serious Total, serious adverse events | 76 / 111 |
Outcome results
Primary
Participants With Adverse Events (AEs)
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
Population: The ITT dataset, which comprised of data from all enrolled participants who had observations at Baseline and at least one Post-Baseline visit, were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tolvaptan | Participants With Adverse Events (AEs) | Participants with TEAEs | 105 participants |
| Tolvaptan | Participants With Adverse Events (AEs) | Participants with serious TEAEs | 76 participants |
| Tolvaptan | Participants With Adverse Events (AEs) | Participants with severe TEAEs | 73 participants |
| Tolvaptan | Participants With Adverse Events (AEs) | Participants discontinued IMP due to TEAE | 19 participants |
| Tolvaptan | Participants With Adverse Events (AEs) | Participants discontinued IMP due to TEAE/death | 28 participants |
| Tolvaptan | Participants With Adverse Events (AEs) | Deaths | 19 participants |
Primary
Participants With Body Weight Abnormalities Reported as TEAEs
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
Population: The ITT dataset, which comprised of data from all enrolled participants who had observations at Baseline and at least one Post-Baseline visit, were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tolvaptan | Participants With Body Weight Abnormalities Reported as TEAEs | Increased weight | 5 participants |
| Tolvaptan | Participants With Body Weight Abnormalities Reported as TEAEs | Decreased weight | 1 participants |
Primary
Participants With Electrocardiogram (ECG) Related Abnormalities Reported as TEAEs
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
Population: The ITT dataset, which comprised of data from all enrolled participants who had observations at Baseline and at least one Post-Baseline visit, were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tolvaptan | Participants With Electrocardiogram (ECG) Related Abnormalities Reported as TEAEs | Atrial fibrillation | 6 participants |
| Tolvaptan | Participants With Electrocardiogram (ECG) Related Abnormalities Reported as TEAEs | Tachycardia | 4 participants |
| Tolvaptan | Participants With Electrocardiogram (ECG) Related Abnormalities Reported as TEAEs | Atrial tachycardia | 3 participants |
| Tolvaptan | Participants With Electrocardiogram (ECG) Related Abnormalities Reported as TEAEs | First degree atrioventricular block | 2 participants |
| Tolvaptan | Participants With Electrocardiogram (ECG) Related Abnormalities Reported as TEAEs | Bradycardia | 2 participants |
| Tolvaptan | Participants With Electrocardiogram (ECG) Related Abnormalities Reported as TEAEs | Sinus tachycardia | 2 participants |
| Tolvaptan | Participants With Electrocardiogram (ECG) Related Abnormalities Reported as TEAEs | Ventricular tachycardia | 2 participants |
| Tolvaptan | Participants With Electrocardiogram (ECG) Related Abnormalities Reported as TEAEs | Left bundle branch block | 1 participants |
| Tolvaptan | Participants With Electrocardiogram (ECG) Related Abnormalities Reported as TEAEs | Tachyarrhythmia | 1 participants |
| Tolvaptan | Participants With Electrocardiogram (ECG) Related Abnormalities Reported as TEAEs | Ventricular arrhythmia | 1 participants |
| Tolvaptan | Participants With Electrocardiogram (ECG) Related Abnormalities Reported as TEAEs | Atrial flutter | 1 participants |
| Tolvaptan | Participants With Electrocardiogram (ECG) Related Abnormalities Reported as TEAEs | ECG ST segment depression | 1 participants |
| Tolvaptan | Participants With Electrocardiogram (ECG) Related Abnormalities Reported as TEAEs | Arrhythmia | 1 participants |
Primary
Participants With Laboratory Values Abnormalities Reported as TEAEs
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
Population: The ITT dataset, which comprised of data from all enrolled participants who had observations at Baseline and at least one Post-Baseline visit, were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tolvaptan | Participants With Laboratory Values Abnormalities Reported as TEAEs | Serum Chemistry-Blood creatinine increased | 4 participants |
| Tolvaptan | Participants With Laboratory Values Abnormalities Reported as TEAEs | Serum Chemistry-Blood potassium increased | 4 participants |
| Tolvaptan | Participants With Laboratory Values Abnormalities Reported as TEAEs | Serum Chemistry-Blood glucose increased | 3 participants |
| Tolvaptan | Participants With Laboratory Values Abnormalities Reported as TEAEs | Serum Chemistry-Blood potassium decreased | 3 participants |
| Tolvaptan | Participants With Laboratory Values Abnormalities Reported as TEAEs | SerumChemistry-Aspartate aminotransferaseincreased | 2 participants |
| Tolvaptan | Participants With Laboratory Values Abnormalities Reported as TEAEs | Serum Chemistry-Blood cholesterol increased | 3 participants |
| Tolvaptan | Participants With Laboratory Values Abnormalities Reported as TEAEs | Serum Chemistry-Blood sodium increased | 2 participants |
| Tolvaptan | Participants With Laboratory Values Abnormalities Reported as TEAEs | Serum Chemistry-Hepatic enzyme increased | 2 participants |
| Tolvaptan | Participants With Laboratory Values Abnormalities Reported as TEAEs | Serum Chemistry-Oxygen saturation decreased | 2 participants |
| Tolvaptan | Participants With Laboratory Values Abnormalities Reported as TEAEs | Serum Chemistry-Hyperglycaemia | 5 participants |
| Tolvaptan | Participants With Laboratory Values Abnormalities Reported as TEAEs | Serum Chemistry-Hyperkalaemia | 7 participants |
| Tolvaptan | Participants With Laboratory Values Abnormalities Reported as TEAEs | Serum Chemistry-Hyperlipidaemia | 4 participants |
| Tolvaptan | Participants With Laboratory Values Abnormalities Reported as TEAEs | Serum Chemistry-Hypernatraemia | 4 participants |
| Tolvaptan | Participants With Laboratory Values Abnormalities Reported as TEAEs | Serum Chemistry-Hyperuricaemia | 3 participants |
| Tolvaptan | Participants With Laboratory Values Abnormalities Reported as TEAEs | Serum Chemistry-Hypoglycaemia | 5 participants |
| Tolvaptan | Participants With Laboratory Values Abnormalities Reported as TEAEs | Serum Chemistry-Hypokalaemia | 14 participants |
| Tolvaptan | Participants With Laboratory Values Abnormalities Reported as TEAEs | Serum Chemistry-Hypomagnesaemia | 3 participants |
| Tolvaptan | Participants With Laboratory Values Abnormalities Reported as TEAEs | Serum Chemistry-Hypoatraemia | 25 participants |
| Tolvaptan | Participants With Laboratory Values Abnormalities Reported as TEAEs | Hematology-Anemia | 20 participants |
| Tolvaptan | Participants With Laboratory Values Abnormalities Reported as TEAEs | Hematology-Thrombocytopenia | 2 participants |
| Tolvaptan | Participants With Laboratory Values Abnormalities Reported as TEAEs | Hematology-International normalized ratioincreased | 4 participants |
| Tolvaptan | Participants With Laboratory Values Abnormalities Reported as TEAEs | Hematology-White blood cell count increased | 2 participants |
Primary
Participants With Vital Signs Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs)
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
Population: The intent-to-treat (ITT) dataset, which comprised of data from all enrolled participants who had observations at Baseline and at least one Post-Baseline visit, were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tolvaptan | Participants With Vital Signs Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs) | Hypotension | 13 participants |
| Tolvaptan | Participants With Vital Signs Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs) | Hypertension | 8 participants |
| Tolvaptan | Participants With Vital Signs Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs) | Pyrexia | 6 participants |
| Tolvaptan | Participants With Vital Signs Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs) | Increased body temperature | 3 participants |
| Tolvaptan | Participants With Vital Signs Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs) | Palpitations | 2 participants |
| Tolvaptan | Participants With Vital Signs Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs) | Increased central venous pressure | 2 participants |
| Tolvaptan | Participants With Vital Signs Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs) | Increased venous pressure | 1 participants |
| Tolvaptan | Participants With Vital Signs Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs) | Orthostatic hypotension | 1 participants |
| Tolvaptan | Participants With Vital Signs Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs) | Hypertensive crisis | 1 participants |
| Tolvaptan | Participants With Vital Signs Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs) | Decreased orthostatic blood pressure | 1 participants |
| Tolvaptan | Participants With Vital Signs Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs) | Increased weight | 5 participants |
| Tolvaptan | Participants With Vital Signs Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs) | Decreased weight | 1 participants |
Secondary
Change From Baseline in Percentage of Participants With Mild Hyponatremia
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
Population: The ITT dataset, which comprised of data from all enrolled participants who had observations at Baseline and at least one Post-Baseline visit, were analyzed. In the last observation carried forward (LOCF) dataset, missing data were filled in using the participant's preceding non-missing value, except that Baseline value will not be carried forward.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tolvaptan | Change From Baseline in Percentage of Participants With Mild Hyponatremia | Day 1 post-dose (N=99) | 53.5 percentage of participants |
| Tolvaptan | Change From Baseline in Percentage of Participants With Mild Hyponatremia | Day 31 (N=110) | 33.6 percentage of participants |
| Tolvaptan | Change From Baseline in Percentage of Participants With Mild Hyponatremia | Week 10 (N=110) | 28.2 percentage of participants |
| Tolvaptan | Change From Baseline in Percentage of Participants With Mild Hyponatremia | Week 18 (N=110) | 33.6 percentage of participants |
| Tolvaptan | Change From Baseline in Percentage of Participants With Mild Hyponatremia | Week 26 (N=110) | 30.9 percentage of participants |
| Tolvaptan | Change From Baseline in Percentage of Participants With Mild Hyponatremia | Week 34 (N=110) | 26.4 percentage of participants |
| Tolvaptan | Change From Baseline in Percentage of Participants With Mild Hyponatremia | Week 42 (N=110) | 26.4 percentage of participants |
| Tolvaptan | Change From Baseline in Percentage of Participants With Mild Hyponatremia | Week 50 (N=110) | 31.8 percentage of participants |
| Tolvaptan | Change From Baseline in Percentage of Participants With Mild Hyponatremia | Week 58 (N=110) | 26.4 percentage of participants |
| Tolvaptan | Change From Baseline in Percentage of Participants With Mild Hyponatremia | Week 70 (N=110) | 30.9 percentage of participants |
| Tolvaptan | Change From Baseline in Percentage of Participants With Mild Hyponatremia | Week 82 (N=110) | 31.8 percentage of participants |
| Tolvaptan | Change From Baseline in Percentage of Participants With Mild Hyponatremia | Week 94 (N=110) | 28.2 percentage of participants |
| Tolvaptan | Change From Baseline in Percentage of Participants With Mild Hyponatremia | Week 106 (N=110) | 27.3 percentage of participants |
| Tolvaptan | Change From Baseline in Percentage of Participants With Mild Hyponatremia | Week 118 (N=110) | 28.2 percentage of participants |
| Tolvaptan | Change From Baseline in Percentage of Participants With Mild Hyponatremia | Week 130 (N=110) | 29.1 percentage of participants |
| Tolvaptan | Change From Baseline in Percentage of Participants With Mild Hyponatremia | Week 142 (N=110) | 25.5 percentage of participants |
| Tolvaptan | Change From Baseline in Percentage of Participants With Mild Hyponatremia | Week 154 (N=110) | 25.5 percentage of participants |
| Tolvaptan | Change From Baseline in Percentage of Participants With Mild Hyponatremia | Week 190 (N=110) | 30.9 percentage of participants |
| Tolvaptan | Change From Baseline in Percentage of Participants With Mild Hyponatremia | Week 202 (N=110) | 30.9 percentage of participants |
| Tolvaptan | Change From Baseline in Percentage of Participants With Mild Hyponatremia | Week 214 (N=110) | 30.9 percentage of participants |
| Tolvaptan | Change From Baseline in Percentage of Participants With Mild Hyponatremia | Week 166 (N=110) | 30.9 percentage of participants |
| Tolvaptan | Change From Baseline in Percentage of Participants With Mild Hyponatremia | Week 178 (N=110) | 30.9 percentage of participants |
Secondary
Change From Baseline in Percentage of Participants With Normal Sodium Levels
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
Population: The ITT dataset, which comprised of data from all enrolled participants who had observations at Baseline and at least one Post-Baseline visit, were analyzed. In the last observation carried forward (LOCF) dataset, missing data were filled in using the participant's preceding non-missing value, except that Baseline value will not be carried forward.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tolvaptan | Change From Baseline in Percentage of Participants With Normal Sodium Levels | Day 1 post-dose (N=99) | 26.3 percentage of participants |
| Tolvaptan | Change From Baseline in Percentage of Participants With Normal Sodium Levels | Day 31 (N=110) | 57.3 percentage of participants |
| Tolvaptan | Change From Baseline in Percentage of Participants With Normal Sodium Levels | Week 10 (N=110) | 60.0 percentage of participants |
| Tolvaptan | Change From Baseline in Percentage of Participants With Normal Sodium Levels | Week 18 (N=110) | 52.7 percentage of participants |
| Tolvaptan | Change From Baseline in Percentage of Participants With Normal Sodium Levels | Week 50 (N=110) | 57.3 percentage of participants |
| Tolvaptan | Change From Baseline in Percentage of Participants With Normal Sodium Levels | Week 58 (N=110) | 60.0 percentage of participants |
| Tolvaptan | Change From Baseline in Percentage of Participants With Normal Sodium Levels | Week 70 (N=110) | 56.4 percentage of participants |
| Tolvaptan | Change From Baseline in Percentage of Participants With Normal Sodium Levels | Week 82 (N=110) | 57.3 percentage of participants |
| Tolvaptan | Change From Baseline in Percentage of Participants With Normal Sodium Levels | Week 94 (N=110) | 60.9 percentage of participants |
| Tolvaptan | Change From Baseline in Percentage of Participants With Normal Sodium Levels | Week 106 (N=110) | 60.0 percentage of participants |
| Tolvaptan | Change From Baseline in Percentage of Participants With Normal Sodium Levels | Week 118 (N=110) | 59.1 percentage of participants |
| Tolvaptan | Change From Baseline in Percentage of Participants With Normal Sodium Levels | Week 130 (N=110) | 59.1 percentage of participants |
| Tolvaptan | Change From Baseline in Percentage of Participants With Normal Sodium Levels | Week 142 (N=110) | 62.7 percentage of participants |
| Tolvaptan | Change From Baseline in Percentage of Participants With Normal Sodium Levels | Week 154 (N=110) | 62.7 percentage of participants |
| Tolvaptan | Change From Baseline in Percentage of Participants With Normal Sodium Levels | Week 166 (N=110) | 57.3 percentage of participants |
| Tolvaptan | Change From Baseline in Percentage of Participants With Normal Sodium Levels | Week 178 (N=110) | 57.3 percentage of participants |
| Tolvaptan | Change From Baseline in Percentage of Participants With Normal Sodium Levels | Week 190 (N=110) | 57.3 percentage of participants |
| Tolvaptan | Change From Baseline in Percentage of Participants With Normal Sodium Levels | Week 202 (N=110) | 58.2 percentage of participants |
| Tolvaptan | Change From Baseline in Percentage of Participants With Normal Sodium Levels | Week 214 (N=110) | 57.3 percentage of participants |
| Tolvaptan | Change From Baseline in Percentage of Participants With Normal Sodium Levels | Week 26 (N=110) | 52.7 percentage of participants |
| Tolvaptan | Change From Baseline in Percentage of Participants With Normal Sodium Levels | Week 34 (N=110) | 59.1 percentage of participants |
| Tolvaptan | Change From Baseline in Percentage of Participants With Normal Sodium Levels | Week 42 (N=110) | 60.9 percentage of participants |
Secondary
Change From Baseline in Percentage of Participants With Severe Hyponatremia
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
Population: The ITT dataset, which comprised of data from all enrolled participants who had observations at Baseline and at least one Post-Baseline visit, were analyzed. In the last observation carried forward (LOCF) dataset, missing data were filled in using the participant's preceding non-missing value, except that Baseline value will not be carried forward.
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| Tolvaptan | Change From Baseline in Percentage of Participants With Severe Hyponatremia | Day 1 post-dose (N=99) | 20.2 percentage of participants | 3 |
| Tolvaptan | Change From Baseline in Percentage of Participants With Severe Hyponatremia | Day 31 (N=110) | 9.1 percentage of participants | 5.1 |
| Tolvaptan | Change From Baseline in Percentage of Participants With Severe Hyponatremia | Week 10 (N=110) | 11.8 percentage of participants | 5 |
| Tolvaptan | Change From Baseline in Percentage of Participants With Severe Hyponatremia | Week 18 (N=110) | 13.6 percentage of participants | 4 |
| Tolvaptan | Change From Baseline in Percentage of Participants With Severe Hyponatremia | Week 26 (N=110) | 16.4 percentage of participants | 4.6 |
| Tolvaptan | Change From Baseline in Percentage of Participants With Severe Hyponatremia | Week 34 (N=110) | 14.5 percentage of participants | 5.6 |
| Tolvaptan | Change From Baseline in Percentage of Participants With Severe Hyponatremia | Week 42 (N=110) | 12.7 percentage of participants | 4.1 |
| Tolvaptan | Change From Baseline in Percentage of Participants With Severe Hyponatremia | Week 50 (N=110) | 10.9 percentage of participants | 4.5 |
| Tolvaptan | Change From Baseline in Percentage of Participants With Severe Hyponatremia | Week 58 (N=110) | 13.6 percentage of participants | 5.1 |
| Tolvaptan | Change From Baseline in Percentage of Participants With Severe Hyponatremia | Week 70 (N=110) | 12.7 percentage of participants | 4.6 |
| Tolvaptan | Change From Baseline in Percentage of Participants With Severe Hyponatremia | Week 82 (N=110) | 10.9 percentage of participants | 4.1 |
| Tolvaptan | Change From Baseline in Percentage of Participants With Severe Hyponatremia | Week 94 (N=110) | 10.9 percentage of participants | 4.8 |
| Tolvaptan | Change From Baseline in Percentage of Participants With Severe Hyponatremia | Week 106 (N=110) | 12.7 percentage of participants | 4.7 |
| Tolvaptan | Change From Baseline in Percentage of Participants With Severe Hyponatremia | Week 118 (N=110) | 12.7 percentage of participants | 4.4 |
| Tolvaptan | Change From Baseline in Percentage of Participants With Severe Hyponatremia | Week 130 (N=110) | 11.8 percentage of participants | 4.7 |
| Tolvaptan | Change From Baseline in Percentage of Participants With Severe Hyponatremia | Week 142 (N=110) | 11.8 percentage of participants | 4.5 |
| Tolvaptan | Change From Baseline in Percentage of Participants With Severe Hyponatremia | Week 154 (N=110) | 11.8 percentage of participants | 4.4 |
| Tolvaptan | Change From Baseline in Percentage of Participants With Severe Hyponatremia | Week 166 (N=110) | 11.8 percentage of participants | 4.5 |
| Tolvaptan | Change From Baseline in Percentage of Participants With Severe Hyponatremia | Week 178 (N=110) | 11.8 percentage of participants | 4.5 |
| Tolvaptan | Change From Baseline in Percentage of Participants With Severe Hyponatremia | Week 190 (N=110) | 11.8 percentage of participants | 4.7 |
| Tolvaptan | Change From Baseline in Percentage of Participants With Severe Hyponatremia | Week 202 (N=110) | 11.8 percentage of participants | 4.6 |
| Tolvaptan | Change From Baseline in Percentage of Participants With Severe Hyponatremia | Week 214 (N=110) | 11.8 percentage of participants | 4.6 |
Secondary
Change From Baseline in the Hyponatremia Disease-specific Survey
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
Population: The Hyponatremia Disease-specific Survey PCS and MCS scores evaluated during the trial were variable with only nominal changes from baseline observed. The data were collected under 2 different datasets, so the number of participants in each dataset was reduced that limited analysis of this endpoint.
Secondary
Mean Change From Baseline in Body Weight by Visit for Those Participants Who Had Clinical Evidence of Hypervolemia at Baseline
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
Population: The ITT dataset comprised of data from all enrolled participants who had observations at Baseline and at least one Post-Baseline visit were analyzed. The observed cases (OC) dataset consisted of only data points obtained from participants who were evaluated at the visit, without missing study drug consecutively for 14 days.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tolvaptan | Mean Change From Baseline in Body Weight by Visit for Those Participants Who Had Clinical Evidence of Hypervolemia at Baseline | Day 31 (N= 26) | -0.5 kg | Standard Deviation 4.6 |
| Tolvaptan | Mean Change From Baseline in Body Weight by Visit for Those Participants Who Had Clinical Evidence of Hypervolemia at Baseline | Week 10 (N= 32) | -1.1 kg | Standard Deviation 3.7 |
| Tolvaptan | Mean Change From Baseline in Body Weight by Visit for Those Participants Who Had Clinical Evidence of Hypervolemia at Baseline | Week 18 (N= 27) | 0.2 kg | Standard Deviation 3 |
| Tolvaptan | Mean Change From Baseline in Body Weight by Visit for Those Participants Who Had Clinical Evidence of Hypervolemia at Baseline | Week 26 (N= 27) | 0.4 kg | Standard Deviation 5.4 |
| Tolvaptan | Mean Change From Baseline in Body Weight by Visit for Those Participants Who Had Clinical Evidence of Hypervolemia at Baseline | Week 34 (N= 26) | 0.5 kg | Standard Deviation 4 |
| Tolvaptan | Mean Change From Baseline in Body Weight by Visit for Those Participants Who Had Clinical Evidence of Hypervolemia at Baseline | Week 42 (N= 24) | 0.3 kg | Standard Deviation 4.6 |
| Tolvaptan | Mean Change From Baseline in Body Weight by Visit for Those Participants Who Had Clinical Evidence of Hypervolemia at Baseline | Week 94 (N= 18) | 3.0 kg | Standard Deviation 8 |
| Tolvaptan | Mean Change From Baseline in Body Weight by Visit for Those Participants Who Had Clinical Evidence of Hypervolemia at Baseline | Week 106 (N= 15) | 1.4 kg | Standard Deviation 8 |
| Tolvaptan | Mean Change From Baseline in Body Weight by Visit for Those Participants Who Had Clinical Evidence of Hypervolemia at Baseline | Week 118 (N= 13) | 2.2 kg | Standard Deviation 8.1 |
| Tolvaptan | Mean Change From Baseline in Body Weight by Visit for Those Participants Who Had Clinical Evidence of Hypervolemia at Baseline | Week 130 (N= 13) | 3.0 kg | Standard Deviation 9 |
| Tolvaptan | Mean Change From Baseline in Body Weight by Visit for Those Participants Who Had Clinical Evidence of Hypervolemia at Baseline | Week 142 (N= 12) | 3.8 kg | Standard Deviation 8.7 |
| Tolvaptan | Mean Change From Baseline in Body Weight by Visit for Those Participants Who Had Clinical Evidence of Hypervolemia at Baseline | Week 154 (N= 11) | 2.7 kg | Standard Deviation 7.9 |
| Tolvaptan | Mean Change From Baseline in Body Weight by Visit for Those Participants Who Had Clinical Evidence of Hypervolemia at Baseline | Week 166 (N= 9) | 2.9 kg | Standard Deviation 9.4 |
| Tolvaptan | Mean Change From Baseline in Body Weight by Visit for Those Participants Who Had Clinical Evidence of Hypervolemia at Baseline | Week 178 (N= 7) | 3.2 kg | Standard Deviation 8.6 |
| Tolvaptan | Mean Change From Baseline in Body Weight by Visit for Those Participants Who Had Clinical Evidence of Hypervolemia at Baseline | Week 190 (N= 5) | -2.4 kg | Standard Deviation 4.5 |
| Tolvaptan | Mean Change From Baseline in Body Weight by Visit for Those Participants Who Had Clinical Evidence of Hypervolemia at Baseline | Week 202 (N= 2) | -7.1 kg | Standard Deviation 0.4 |
| Tolvaptan | Mean Change From Baseline in Body Weight by Visit for Those Participants Who Had Clinical Evidence of Hypervolemia at Baseline | Week 214 (N= 2) | -8.5 kg | Standard Deviation 1.6 |
| Tolvaptan | Mean Change From Baseline in Body Weight by Visit for Those Participants Who Had Clinical Evidence of Hypervolemia at Baseline | Week 50 (N= 22) | 1.0 kg | Standard Deviation 4.7 |
| Tolvaptan | Mean Change From Baseline in Body Weight by Visit for Those Participants Who Had Clinical Evidence of Hypervolemia at Baseline | Week 58 (N= 22) | 1.7 kg | Standard Deviation 4.5 |
| Tolvaptan | Mean Change From Baseline in Body Weight by Visit for Those Participants Who Had Clinical Evidence of Hypervolemia at Baseline | Week 70 (N= 18) | 1.7 kg | Standard Deviation 5.2 |
| Tolvaptan | Mean Change From Baseline in Body Weight by Visit for Those Participants Who Had Clinical Evidence of Hypervolemia at Baseline | Week 82 (N= 18) | 2.0 kg | Standard Deviation 7 |
Comparison: Statistical analysis at Day 31p-value: 0.4922Student's t-test
Comparison: Statistical analysis at Week 10p-value: 0.1054Student's t-test
Comparison: Statistical analysis at Week 18p-value: 0.7656Student's t-test
Comparison: Statistical analysis at Week 26p-value: 0.7084Student's t-test
Comparison: Statistical analysis at Week 34p-value: 0.5138Student's t-test
Comparison: Statistical analysis at Week 42p-value: 0.7175Student's t-test
Comparison: Statistical analysis at Week 50p-value: 0.354Student's t-test
Comparison: Statistical analysis at Week 58p-value: 0.0852Student's t-test
Comparison: Statistical analysis at Week 70p-value: 0.1923Student's t-test
Comparison: Statistical analysis at Week 82p-value: 0.2335Student's t-test
Comparison: Statistical analysis at Week 94p-value: 0.1346Student's t-test
Comparison: Statistical analysis at Week 106p-value: 0.5237Student's t-test
Comparison: Statistical analysis at Week 118p-value: 0.3476Student's t-test
Comparison: Statistical analysis at Week 130p-value: 0.2488Student's t-test
Comparison: Statistical analysis at Week 142p-value: 0.1598Student's t-test
Comparison: Statistical analysis at Week 154p-value: 0.282Student's t-test
Comparison: Statistical analysis at Week 166p-value: 0.3743Student's t-test
Comparison: Statistical analysis at Week 178p-value: 0.36Student's t-test
Comparison: Statistical analysis at Week 190p-value: 0.3101Student's t-test
Comparison: Statistical analysis at Week 202p-value: 0.0269Student's t-test
Comparison: Statistical analysis at Week 214p-value: 0.0944Student's t-test
Secondary
Mean Change From Baseline in Serum Sodium Measurements
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
Population: The ITT dataset, which comprised of data from all enrolled participants who had observations at Baseline and at least one Post-Baseline visit, were analyzed. In the last observation carried forward (LOCF) dataset, missing data were filled in using the participant's preceding non-missing value, except that Baseline value will not be carried forward.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tolvaptan | Mean Change From Baseline in Serum Sodium Measurements | Day 1 post-dose (N= 99) | 2.2 mEq/L | Standard Deviation 3.3 |
| Tolvaptan | Mean Change From Baseline in Serum Sodium Measurements | Day 14 (N= 110) | 5.2 mEq/L | Standard Deviation 5.5 |
| Tolvaptan | Mean Change From Baseline in Serum Sodium Measurements | Day 31 (N= 110) | 5.0 mEq/L | Standard Deviation 4.8 |
| Tolvaptan | Mean Change From Baseline in Serum Sodium Measurements | Week 10 (N= 110) | 5.0 mEq/L | Standard Deviation 5.1 |
| Tolvaptan | Mean Change From Baseline in Serum Sodium Measurements | Week 18 (N= 110) | 4.6 mEq/L | Standard Deviation 5.4 |
| Tolvaptan | Mean Change From Baseline in Serum Sodium Measurements | Week 26 (N= 110) | 4.2 mEq/L | Standard Deviation 5.7 |
| Tolvaptan | Mean Change From Baseline in Serum Sodium Measurements | Week 34 (N= 110) | 4.7 mEq/L | Standard Deviation 5.9 |
| Tolvaptan | Mean Change From Baseline in Serum Sodium Measurements | Week 42 (N= 110) | 5.2 mEq/L | Standard Deviation 5.6 |
| Tolvaptan | Mean Change From Baseline in Serum Sodium Measurements | Week 50 (N= 110) | 5.0 mEq/L | Standard Deviation 5.9 |
| Tolvaptan | Mean Change From Baseline in Serum Sodium Measurements | Week 58 (N= 110) | 5.0 mEq/L | Standard Deviation 5.9 |
| Tolvaptan | Mean Change From Baseline in Serum Sodium Measurements | Week 70 (N= 110) | 4.8 mEq/L | Standard Deviation 5.8 |
| Tolvaptan | Mean Change From Baseline in Serum Sodium Measurements | Week 82 (N= 110) | 4.8 mEq/L | Standard Deviation 5.7 |
| Tolvaptan | Mean Change From Baseline in Serum Sodium Measurements | Week 94 (N= 110) | 5.1 mEq/L | Standard Deviation 5.8 |
| Tolvaptan | Mean Change From Baseline in Serum Sodium Measurements | Week 106 (N= 110) | 5.0 mEq/L | Standard Deviation 6 |
| Tolvaptan | Mean Change From Baseline in Serum Sodium Measurements | Week 118 (N= 110) | 4.8 mEq/L | Standard Deviation 5.9 |
| Tolvaptan | Mean Change From Baseline in Serum Sodium Measurements | Week 130 (N= 110) | 4.9 mEq/L | Standard Deviation 6 |
| Tolvaptan | Mean Change From Baseline in Serum Sodium Measurements | Week 142 (N= 110) | 5.2 mEq/L | Standard Deviation 5.9 |
| Tolvaptan | Mean Change From Baseline in Serum Sodium Measurements | Week 154 (N= 110) | 5.2 mEq/L | Standard Deviation 5.9 |
| Tolvaptan | Mean Change From Baseline in Serum Sodium Measurements | Week 166 (N= 110) | 4.9 mEq/L | Standard Deviation 5.8 |
| Tolvaptan | Mean Change From Baseline in Serum Sodium Measurements | Week 178 (N= 110) | 4.8 mEq/L | Standard Deviation 5.9 |
| Tolvaptan | Mean Change From Baseline in Serum Sodium Measurements | Week 190 (N= 110) | 5.1 mEq/L | Standard Deviation 6.1 |
| Tolvaptan | Mean Change From Baseline in Serum Sodium Measurements | Week 202 (N= 110) | 5.0 mEq/L | Standard Deviation 5.9 |
| Tolvaptan | Mean Change From Baseline in Serum Sodium Measurements | Week 214 (N= 110) | 5.0 mEq/L | Standard Deviation 5.9 |
p-value: <0.0001Student's t-test
p-value: <0.0001Student's t-test
p-value: <0.0001Student's t-test
p-value: <0.0001Student's t-test
p-value: <0.0001Student's t-test
p-value: <0.0001Student's t-test
p-value: <0.0001Student's t-test
p-value: <0.0001Student's t-test
p-value: <0.0001Student's t-test
p-value: <0.0001Student's t-test
p-value: <0.0001Student's t-test
p-value: <0.0001Student's t-test
p-value: <0.0001Student's t-test
p-value: <0.0001Student's t-test
p-value: <0.0001Student's t-test
p-value: <0.0001Student's t-test
p-value: <0.0001Student's t-test
p-value: <0.0001Student's t-test
p-value: <0.0001Student's t-test
p-value: <0.0001Student's t-test
p-value: <0.0001Student's t-test
p-value: <0.0001Student's t-test
p-value: <0.0001Student's t-test
Secondary
Mean Change From Baseline in SF-12 (Health Survey) Mental Component Summary (MCS)
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
Population: The ITT dataset comprised of data from all enrolled participants who had observations at Baseline and at least one Post-Baseline visit were analyzed. In the last observation carried forward (LOCF) dataset, missing data were filled in using the participant's preceding non-missing value, except that Baseline value will not be carried forward.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tolvaptan | Mean Change From Baseline in SF-12 (Health Survey) Mental Component Summary (MCS) | Week 202 (N= 1) | -0.8 Units on a scale | — |
| Tolvaptan | Mean Change From Baseline in SF-12 (Health Survey) Mental Component Summary (MCS) | Week 214 (N= 6) | -0.5 Units on a scale | Standard Deviation 7.8 |
| Tolvaptan | Mean Change From Baseline in SF-12 (Health Survey) Mental Component Summary (MCS) | Day 14 (N= 102) | -1.0 Units on a scale | Standard Deviation 8.8 |
| Tolvaptan | Mean Change From Baseline in SF-12 (Health Survey) Mental Component Summary (MCS) | Day 31 (N= 106) | -1.0 Units on a scale | Standard Deviation 9.6 |
| Tolvaptan | Mean Change From Baseline in SF-12 (Health Survey) Mental Component Summary (MCS) | Week 10 (N= 106) | -0.4 Units on a scale | Standard Deviation 9.8 |
| Tolvaptan | Mean Change From Baseline in SF-12 (Health Survey) Mental Component Summary (MCS) | Week 18 (N= 106) | -2.0 Units on a scale | Standard Deviation 8.8 |
| Tolvaptan | Mean Change From Baseline in SF-12 (Health Survey) Mental Component Summary (MCS) | Week 26 (N= 106) | -1.1 Units on a scale | Standard Deviation 8.8 |
| Tolvaptan | Mean Change From Baseline in SF-12 (Health Survey) Mental Component Summary (MCS) | Week 34 (N= 106) | -2.7 Units on a scale | Standard Deviation 9.4 |
| Tolvaptan | Mean Change From Baseline in SF-12 (Health Survey) Mental Component Summary (MCS) | Week 42 (N= 106) | -2.1 Units on a scale | Standard Deviation 10.1 |
| Tolvaptan | Mean Change From Baseline in SF-12 (Health Survey) Mental Component Summary (MCS) | Week 50 (N= 106) | -1.9 Units on a scale | Standard Deviation 10.4 |
| Tolvaptan | Mean Change From Baseline in SF-12 (Health Survey) Mental Component Summary (MCS) | Week 58 (N= 106) | -2.5 Units on a scale | Standard Deviation 11.4 |
| Tolvaptan | Mean Change From Baseline in SF-12 (Health Survey) Mental Component Summary (MCS) | Week 70 (N= 106) | -2.6 Units on a scale | Standard Deviation 10.7 |
| Tolvaptan | Mean Change From Baseline in SF-12 (Health Survey) Mental Component Summary (MCS) | Week 82 (N= 106) | -2.5 Units on a scale | Standard Deviation 10.5 |
| Tolvaptan | Mean Change From Baseline in SF-12 (Health Survey) Mental Component Summary (MCS) | Week 94 (N= 106) | -2.6 Units on a scale | Standard Deviation 10.5 |
| Tolvaptan | Mean Change From Baseline in SF-12 (Health Survey) Mental Component Summary (MCS) | Week 106 (N= 106) | -3.7 Units on a scale | Standard Deviation 11.6 |
| Tolvaptan | Mean Change From Baseline in SF-12 (Health Survey) Mental Component Summary (MCS) | Week 142 (N= 2) | -11.2 Units on a scale | Standard Deviation 27.6 |
| Tolvaptan | Mean Change From Baseline in SF-12 (Health Survey) Mental Component Summary (MCS) | Week 166 (N= 2) | 5.0 Units on a scale | Standard Deviation 13.6 |
| Tolvaptan | Mean Change From Baseline in SF-12 (Health Survey) Mental Component Summary (MCS) | Week 178 (N= 2) | 0.4 Units on a scale | Standard Deviation 4.5 |
| Tolvaptan | Mean Change From Baseline in SF-12 (Health Survey) Mental Component Summary (MCS) | Week 190 (N= 6) | -2.8 Units on a scale | Standard Deviation 8.2 |
Comparison: Statistical analysis at Day 14p-value: 0.2575Student t-test
Comparison: Statistical analysis at Day 31p-value: 0.2715Student's t-test
Comparison: Statistical analysis at Week 10p-value: 0.686Student's t-test
Comparison: Statistical analysis at Week 18p-value: 0.0224Student's t-test
Comparison: Statistical analysis at Week 26p-value: 0.1871Student's t-test
Comparison: Statistical analysis at Week 34p-value: 0.0039Student's t-test
Comparison: Statistical analysis at Week 42p-value: 0.0325Student's t-test
Comparison: Statistical analysis at Week 50p-value: 0.0631Student's t-test
Comparison: Statistical analysis at Week 58p-value: 0.0277Student's t-test
Comparison: Statistical analysis at Week 70p-value: 0.0128Student's t-test
Comparison: Statistical analysis at Week 82p-value: 0.0164Student's t-test
Comparison: Statistical analysis at Week 94p-value: 0.0119Student's t-test
Comparison: Statistical analysis at Week 106p-value: 0.0013Student's t-test
Comparison: Statistical analysis at Week 142p-value: 0.6691Student's t-test
Comparison: Statistical analysis at Week 166p-value: 0.6923Student's t-test
Comparison: Statistical analysis at Week 178p-value: 0.9292Student's t-test
Comparison: Statistical analysis at Week 190p-value: 0.4401Student's t-test
Comparison: Statistical analysis at Week 214p-value: 0.3609Student's t-test
Secondary
Mean Change From Baseline in SF-12 (Health Survey) Physical Component Summary (PCS)
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
Population: The ITT dataset comprised of data from all enrolled participants who had observations at Baseline and at least one Post-Baseline visit were analyzed. In the last observation carried forward (LOCF) dataset, missing data were filled in using the participant's preceding non-missing value, except that Baseline value will not be carried forward.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tolvaptan | Mean Change From Baseline in SF-12 (Health Survey) Physical Component Summary (PCS) | Week 58 (N= 106) | -0.9 Units on a scale | Standard Deviation 9 |
| Tolvaptan | Mean Change From Baseline in SF-12 (Health Survey) Physical Component Summary (PCS) | Week 70 (N= 106) | -1.1 Units on a scale | Standard Deviation 9.1 |
| Tolvaptan | Mean Change From Baseline in SF-12 (Health Survey) Physical Component Summary (PCS) | Week 82 (N= 106) | -0.9 Units on a scale | Standard Deviation 8.9 |
| Tolvaptan | Mean Change From Baseline in SF-12 (Health Survey) Physical Component Summary (PCS) | Week 94 (N= 106) | -1.6 Units on a scale | Standard Deviation 9.1 |
| Tolvaptan | Mean Change From Baseline in SF-12 (Health Survey) Physical Component Summary (PCS) | Week 106 (N= 106) | -1.7 Units on a scale | Standard Deviation 8.4 |
| Tolvaptan | Mean Change From Baseline in SF-12 (Health Survey) Physical Component Summary (PCS) | Week 142 (N= 2) | -9.1 Units on a scale | Standard Deviation 10.8 |
| Tolvaptan | Mean Change From Baseline in SF-12 (Health Survey) Physical Component Summary (PCS) | Week 166 (N= 2) | 4.6 Units on a scale | Standard Deviation 9.7 |
| Tolvaptan | Mean Change From Baseline in SF-12 (Health Survey) Physical Component Summary (PCS) | Week 178 (N= 2) | -11.3 Units on a scale | Standard Deviation 2.5 |
| Tolvaptan | Mean Change From Baseline in SF-12 (Health Survey) Physical Component Summary (PCS) | Day 14 (N= 102) | 1.0 Units on a scale | Standard Deviation 7.3 |
| Tolvaptan | Mean Change From Baseline in SF-12 (Health Survey) Physical Component Summary (PCS) | Day 31 (N= 106) | 0.4 Units on a scale | Standard Deviation 7.9 |
| Tolvaptan | Mean Change From Baseline in SF-12 (Health Survey) Physical Component Summary (PCS) | Week 10 (N= 106) | 0.3 Units on a scale | Standard Deviation 8.1 |
| Tolvaptan | Mean Change From Baseline in SF-12 (Health Survey) Physical Component Summary (PCS) | Week 18 (N= 106) | 0.4 Units on a scale | Standard Deviation 8.1 |
| Tolvaptan | Mean Change From Baseline in SF-12 (Health Survey) Physical Component Summary (PCS) | Week 26 (N= 106) | -0.9 Units on a scale | Standard Deviation 9.7 |
| Tolvaptan | Mean Change From Baseline in SF-12 (Health Survey) Physical Component Summary (PCS) | Week 34 (N= 106) | -0.3 Units on a scale | Standard Deviation 9.4 |
| Tolvaptan | Mean Change From Baseline in SF-12 (Health Survey) Physical Component Summary (PCS) | Week 42 (N= 106) | -1.1 Units on a scale | Standard Deviation 9.4 |
| Tolvaptan | Mean Change From Baseline in SF-12 (Health Survey) Physical Component Summary (PCS) | Week 50 (N= 106) | -1.1 Units on a scale | Standard Deviation 9 |
| Tolvaptan | Mean Change From Baseline in SF-12 (Health Survey) Physical Component Summary (PCS) | Week 190 (N= 6) | -2.2 Units on a scale | Standard Deviation 5.6 |
| Tolvaptan | Mean Change From Baseline in SF-12 (Health Survey) Physical Component Summary (PCS) | Week 214 (N= 6) | 4.0 Units on a scale | Standard Deviation 9.2 |
| Tolvaptan | Mean Change From Baseline in SF-12 (Health Survey) Physical Component Summary (PCS) | Week 202 (N= 1) | 0.6 Units on a scale | — |
Comparison: Statistical analysis at Week 70p-value: 0.2269Student's t-test
Comparison: Statistical analysis at Day 14p-value: 0.1739Student t-test
Comparison: Statistical analysis at Day 31p-value: 0.6095Student's t-test
Comparison: Statistical analysis at Week 10p-value: 0.6902Student's t-test
Comparison: Statistical analysis at Week 18p-value: 0.634Student's t-test
Comparison: Statistical analysis at Week 26p-value: 0.321Student's t-test
Comparison: Statistical analysis at Week 34p-value: 0.7787Student's t-test
Comparison: Statistical analysis at Week 42p-value: 0.2198Student's t-test
Comparison: Statistical analysis at Week 50p-value: 0.1926Student's t-test
Comparison: Statistical analysis at Week 58p-value: 0.3109Student's t-test
Comparison: Statistical analysis at Week 82p-value: 0.2749Student's t-test
Comparison: Statistical analysis at Week 94p-value: 0.0702Student's t-test
Comparison: Statistical analysis at Week 106p-value: 0.0412Student's t-test
Comparison: Statistical analysis at Week 142p-value: 0.4448Student's t-test
Comparison: Statistical analysis at Week 166p-value: 0.6233Student's t-test
Comparison: Statistical analysis at Week 178p-value: 0.1001Student's t-test
Comparison: Statistical analysis at Week 190p-value: 0.3739Student's t-test
Comparison: Statistical analysis at Week 214p-value: 0.3334Student's t-test
Secondary
Number of Participants Requiring Prescription of Hypertonic Saline
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
Population: The ITT dataset, which comprised of data from all enrolled participants who had observations at Baseline and at least one Post-Baseline visit, were analyzed. Percentage of participants requiring prescription of hypertonic saline was not analyzed due to a low number of participants who received the treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tolvaptan | Number of Participants Requiring Prescription of Hypertonic Saline | 2 participants |
Secondary
Percentage of Participants Requiring Prescription of Fluid Restriction
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
Population: The ITT dataset, which comprised of data from all enrolled participants who had observations at Baseline and at least one Post-Baseline visit, were analyzed. In the last observation carried forward (LOCF) dataset, missing data were filled in using the participant's preceding non-missing value, except that Baseline value will not be carried forward.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tolvaptan | Percentage of Participants Requiring Prescription of Fluid Restriction | Mild Hyponatremia (N=76) | 14.47 percentage of participants |
| Tolvaptan | Percentage of Participants Requiring Prescription of Fluid Restriction | Severe Hyponatremia (N=35) | 5.71 percentage of participants |
Secondary
Percentage of Participants Requiring Prescription of Other Medicines
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
Population: The ITT dataset, which comprised of data from all enrolled participants who had observations at Baseline and at least one Post-Baseline visit, were analyzed. Percentage of participants requiring other medicines such as demeclocycline or urea was not analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tolvaptan | Percentage of Participants Requiring Prescription of Other Medicines | 0 percentage of participants |