Heart Failure
Conditions
Keywords
Heart failure, Volume overload, Tolvaptan, loop diuretics
Brief summary
One tolvaptan 15 mg tablet or placebo tablet will be orally administered once daily in the morning for up to 14 days to heart failure patients with volume overload that does not show adequate response to other diuretics such as loop diuretics in order to investigate the effect of tolvaptan on the mid- to long-term prognosis of the target population. The efficacy of tolvaptan during the treatment period will also be investigated.
Interventions
DRUGTolvaptan
Once-daily oral administration of one tolvaptan 15 mg tablet in the morning
DRUGPlacebo of tolvaptan
Once-daily oral administration of one placebo tablet in the morning
Sponsors
Otsuka Pharmaceutical Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
20 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Patients from whom informed consent has been properly obtained in writing prior to start of the trial * Patients who have been clinically diagnosed with heart failure * Patients with any of the following conditions or symptoms: lower limb edema, dyspnea, jugular venous distension, hepatomegaly, pulmonary rales, third heart sound, or pulmonary congestion * Patients who have been receiving loop diuretics, thiazide diuretics, or anti-aldosterone diuretics * Male or female patients of age 20 to 85 years inclusive (at time of informed consent) * Patients who, together with their partner(s), are able to use an appropriate method of contraception until 3 months after final trial drug administration * Patients who are able to be hospitalized at the trial site for at least 7 days from the start of trial drug administration
Exclusion criteria
* Patients with a history of hypersensitivity to any ingredient of the drug or to tolvaptan analogues (e.g., mozavaptan hydrochloride) * Patients with anuria * Patients who cannot sense thirst or who have difficulty with fluid intake * Patients with hypernatremia (serum sodium concentration \> institutional upper limit of normal) 5) Female patients who are pregnant, possibly pregnant, or nursing * Patients judged by the investigator or subinvestigator to be inappropriate for inclusion in the trial due to any of the following conditions or symptoms: * Hyponatremia (serum sodium concentration \< 125 mEq/L) * Serious coronary artery disease or cerebrovascular disease * Hyperkalemia * Severe renal disorder * Poorly controlled diabetes mellitus * Severe hepatic disease * Impaired urinary excretion due to urinary stenosis, calculus, or tumor * Cardiac valve disease with significant heart valve stenosis * Malignant tumor of unfavorable prognosis * Patients with suspected hypovolemia * Patients with an implanted circulatory support device * Patients in whom acute cardiac infarction occurred within 30 days prior to the screening examination * Patients who participated in any other clinical trial or postmarketing clinical trial within 30 days prior to the date of informed consent for the present trial * Patients who received tolvaptan within 26 weeks prior to the date of informed consent * Patients who are otherwise judged by the investigator or sub-investigator to be inappropriate for inclusion in the trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cummulative Incidence of Events at Week 26 | Week 26 | From start day of IMP administration to final day of follow up period, 1) and 2) below were defined as event 1. Death from cardiovascular events 2. Worsening of heart failure * The day of re-hospitalization due to worsening of heart failure * The day of medication below due to worsening of heart failure Phosphodiesterase III inhibitors (Injection), Catecholamine preparations (Injection), Colforsin preparations (Injection), Diuretics (Injection), Human atrial natriuretic peptide preparations (Injection)：Calperitide (Injection) |
| Mortality （Number of Death） | Week26 | Statistical comparison was not done. |
| Body Weight | Day15 | The comparison of the average of amount of change from baseline. Statistical comparison was not done. |
| Number of Subjects Whose Lower Limb Edema Severity Grading Improved by One or More Grade | Day15 | Of the subjects who had lower limb edema at baseline, the number of subjects whose lower limb edema severity grading. Statistical comparison was not done. |
| Jugular Venous Distension | Day15 | The comparison of the average of amount of change from baseline. Statistical comparison was not done. |
| Change in Liver Size From Baseline | Day15 | The comparison of the average of amount of change from baseline. Statistical comparison was not done． |
| Pulmonary Rales | Day15 | Of the subjects who had pulmonary rales at baseline, the number of subjects whose symptom was resolved at completion of treatment. Statistical comparison was not done. |
| Third Heart Sound | Day15 | Of the subjects who had third heart sound at baseline, the number of subjects whose symptom was resolved at completion of treatment. Statistical comparison was not done. |
| Cardiothoracic Ratio | Day15 | Investigator majored Thoracic length and Cardiac length from chest X-ray. Cardiothoracic Ratio was calculated from Cardiac length/Thoracic length\*100. Lowering of Cardiothoracic Ratio suggests recovery from heart congestion. The comparison of the average of amount of change from baseline. Statistical comparison was not done. |
| Pulmonary Congestion | Day15 | Of the subjects who had pulmonary congestion at baseline, the number of subjects whose pulmonary congestion severity grading showed an improvement of one grade or more (eg, moderate to mild) at completion of treatment. Statistical comparison was not done. |
| Plasma Brain Natriuretic Peptide (BNP) Concentration | Day15 | The comparison of the average of amount of change from baseline. Statistical comparison was not done. |
| Dypnea | Day15 | Of the subjects who had dyspnoea at baseline, the number of subjects whose symptom was resolved at completion of treatment. Statistical comparison was not done. |
| Number of Subjects Whose New York Heart Association (NYHA) Classification Improved by One More Grade From Baseline | The day after last IMP administration and Baseline | New York Heart Association (NYHA) Classification is below ClassI：No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea (shortness of breath). ClassII：Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea (shortness of breath). ClassIII：Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes fatigue, palpitation, or dyspnea. ClassIV：Unable to carry on any physical activity without discomfort. Symptoms of heart failure at rest. If any physical activity is undertaken, discomfort increases. |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Tolvaptan 15 mg
Tolvaptan: Once-daily oral administration of one tolvaptan 15 mg tablet in the morning | 50 |
| Placebo Placebo
Placebo of tolvaptan: Once-daily oral administration of one placebo tablet in the morning | 50 |
| Total | 100 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Deviation of exclusion criteria | 1 | 0 |
| Overall Study | Physician Decision | 5 | 3 |
| Overall Study | Protocol Violation | 2 | 0 |
Baseline characteristics
| Characteristic | Placebo | Tolvaptan | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 37 Participants | 41 Participants | 78 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants | 9 Participants | 22 Participants |
| Age, Continuous | 71.7 years STANDARD_DEVIATION 11.2 | 73.8 years STANDARD_DEVIATION 8.4 | 72.8 years STANDARD_DEVIATION 9.9 |
| Region of Enrollment Japan | 50 participants | 50 participants | 100 participants |
| Sex: Female, Male Female | 13 Participants | 21 Participants | 34 Participants |
| Sex: Female, Male Male | 37 Participants | 29 Participants | 66 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 31 / 50 | 7 / 50 |
| serious Total, serious adverse events | 24 / 50 | 22 / 50 |
Outcome results
Primary
Body Weight
The comparison of the average of amount of change from baseline. Statistical comparison was not done.
Time frame: Day15
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tolvaptan | Body Weight | -1.99 kg | Standard Deviation 1.61 |
| Placebo | Body Weight | -1.20 kg | Standard Deviation 1.97 |
Primary
Cardiothoracic Ratio
Investigator majored Thoracic length and Cardiac length from chest X-ray. Cardiothoracic Ratio was calculated from Cardiac length/Thoracic length\*100. Lowering of Cardiothoracic Ratio suggests recovery from heart congestion. The comparison of the average of amount of change from baseline. Statistical comparison was not done.
Time frame: Day15
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tolvaptan | Cardiothoracic Ratio | -2.13 Percentage | Standard Deviation 3.53 |
| Placebo | Cardiothoracic Ratio | -0.83 Percentage | Standard Deviation 3.85 |
Primary
Change in Liver Size From Baseline
The comparison of the average of amount of change from baseline. Statistical comparison was not done．
Time frame: Day15
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tolvaptan | Change in Liver Size From Baseline | -0.20 cm | Standard Deviation 0.52 |
| Placebo | Change in Liver Size From Baseline | -0.19 cm | Standard Deviation 0.55 |
Primary
Cummulative Incidence of Events at Week 26
From start day of IMP administration to final day of follow up period, 1) and 2) below were defined as event 1. Death from cardiovascular events 2. Worsening of heart failure * The day of re-hospitalization due to worsening of heart failure * The day of medication below due to worsening of heart failure Phosphodiesterase III inhibitors (Injection), Catecholamine preparations (Injection), Colforsin preparations (Injection), Diuretics (Injection), Human atrial natriuretic peptide preparations (Injection)：Calperitide (Injection)
Time frame: Week 26
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tolvaptan | Cummulative Incidence of Events at Week 26 | 35.6 Percentage of events at 26 weeks |
| Placebo | Cummulative Incidence of Events at Week 26 | 43.8 Percentage of events at 26 weeks |
Primary
Dypnea
Of the subjects who had dyspnoea at baseline, the number of subjects whose symptom was resolved at completion of treatment. Statistical comparison was not done.
Time frame: Day15
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tolvaptan | Dypnea | 11 participants |
| Placebo | Dypnea | 12 participants |
Primary
Jugular Venous Distension
The comparison of the average of amount of change from baseline. Statistical comparison was not done.
Time frame: Day15
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tolvaptan | Jugular Venous Distension | -0.94 cm | Standard Deviation 2.07 |
| Placebo | Jugular Venous Distension | -1.23 cm | Standard Deviation 2.78 |
Primary
Mortality （Number of Death）
Statistical comparison was not done.
Time frame: Week26
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tolvaptan | Mortality （Number of Death） | 2 participants |
| Placebo | Mortality （Number of Death） | 3 participants |
Primary
Number of Subjects Whose Lower Limb Edema Severity Grading Improved by One or More Grade
Of the subjects who had lower limb edema at baseline, the number of subjects whose lower limb edema severity grading. Statistical comparison was not done.
Time frame: Day15
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tolvaptan | Number of Subjects Whose Lower Limb Edema Severity Grading Improved by One or More Grade | 27 participants |
| Placebo | Number of Subjects Whose Lower Limb Edema Severity Grading Improved by One or More Grade | 16 participants |
Primary
Number of Subjects Whose New York Heart Association (NYHA) Classification Improved by One More Grade From Baseline
New York Heart Association (NYHA) Classification is below ClassI：No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea (shortness of breath). ClassII：Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea (shortness of breath). ClassIII：Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes fatigue, palpitation, or dyspnea. ClassIV：Unable to carry on any physical activity without discomfort. Symptoms of heart failure at rest. If any physical activity is undertaken, discomfort increases.
Time frame: The day after last IMP administration and Baseline
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tolvaptan | Number of Subjects Whose New York Heart Association (NYHA) Classification Improved by One More Grade From Baseline | 22 participants |
| Placebo | Number of Subjects Whose New York Heart Association (NYHA) Classification Improved by One More Grade From Baseline | 24 participants |
Primary
Plasma Brain Natriuretic Peptide (BNP) Concentration
The comparison of the average of amount of change from baseline. Statistical comparison was not done.
Time frame: Day15
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tolvaptan | Plasma Brain Natriuretic Peptide (BNP) Concentration | -72.60 pg/mL | Standard Deviation 268.9 |
| Placebo | Plasma Brain Natriuretic Peptide (BNP) Concentration | -166.96 pg/mL | Standard Deviation 353.34 |
Primary
Pulmonary Congestion
Of the subjects who had pulmonary congestion at baseline, the number of subjects whose pulmonary congestion severity grading showed an improvement of one grade or more (eg, moderate to mild) at completion of treatment. Statistical comparison was not done.
Time frame: Day15
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tolvaptan | Pulmonary Congestion | 24 participants |
| Placebo | Pulmonary Congestion | 20 participants |
Primary
Pulmonary Rales
Of the subjects who had pulmonary rales at baseline, the number of subjects whose symptom was resolved at completion of treatment. Statistical comparison was not done.
Time frame: Day15
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tolvaptan | Pulmonary Rales | 13 participants |
| Placebo | Pulmonary Rales | 9 participants |
Primary
Third Heart Sound
Of the subjects who had third heart sound at baseline, the number of subjects whose symptom was resolved at completion of treatment. Statistical comparison was not done.
Time frame: Day15
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tolvaptan | Third Heart Sound | 8 participants |
| Placebo | Third Heart Sound | 10 participants |