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

Study Overview
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Brief Summary
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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.

Official Title
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International, Multicenter, Study of One-year, Open-label, Titrated Oral Tolvaptan Tablet Administration in Patients With Chronic Hyponatremia: Extension to Studies 156-02-235 and 156-03-238 to Assess One-year Safety

Conditions
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Hyponatremia

Intervention / Treatment
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* Drug: Tolvaptan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age greater than or equal to 18 years. Ability to provide informed consent or assent. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline to Post-Week 214 follow-up visit | 
| 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. | Baseline to Post-Week 214 follow-up visit | 
| 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. | Baseline to Post-Week 214 follow-up visit | 
| 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. | Baseline to Post-Week 214 follow-up visit | 
| 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. | Baseline to Post-Week 214 follow-up visit | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline of parent trial to Week 214 | 
| 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. | Baseline to Week 214 | 
| 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. | Baseline to Week 214 | 
| 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. | Baseline to Week 214 | 
| 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. | Baseline to Post-Week 214 follow-up visit | 
| 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. | Baseline to Post-Week 214 follow-up visit | 
| 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. | Baseline to Post-Week 214 follow-up visit | 
| 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. | Baseline to Week 214 | 
| 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. | Baseline to Week 214 | 
| 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. | Baseline to Week 214 | 
| 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. | Baseline to Week 214 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hyponatremia