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Effect of Tolvaptan on Mid- to Long-term Prognosis of Heart Failure Patients

Primary Purpose

Heart Failure

Status
Completed
Phase
Phase 4
Locations
Japan
Study Type
Interventional
Intervention
Tolvaptan
Placebo of tolvaptan
Sponsored by
Otsuka Pharmaceutical Co., Ltd.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Heart Failure focused on measuring Heart failure, Volume overload, Tolvaptan, loop diuretics

Eligibility Criteria

20 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Tolvaptan

Placebo

Arm Description

15 mg

Placebo

Outcomes

Primary Outcome Measures

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 Death from cardiovascular events 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）
Statistical comparison was not done.
Body Weight
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
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
The comparison of the average of amount of change from baseline. Statistical comparison was not done.
Change in Liver Size From Baseline
The comparison of the average of amount of change from baseline. Statistical comparison was not done．
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.
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.
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.
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.
Plasma Brain Natriuretic Peptide (BNP) Concentration
The comparison of the average of amount of change from baseline. Statistical comparison was not done.
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.
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.

Secondary Outcome Measures

Full Information

First Posted
September 15, 2011
Last Updated
October 3, 2019
Sponsor
Otsuka Pharmaceutical Co., Ltd.
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1. Study Identification

Unique Protocol Identification Number
NCT01439009
Brief Title
Effect of Tolvaptan on Mid- to Long-term Prognosis of Heart Failure Patients
Official Title
A Multi-center,_double-blind,_pararel-group Comparison Trial to Investigate the Effect of Short-term Administration of Tolvaptan on Mid- to Long-term Prognosis of Heart Failure Patients (Phase_4 Study)
Study Type
Interventional

2. Study Status

Record Verification Date
October 2019
Overall Recruitment Status
Completed
Study Start Date
September 2011 (undefined)
Primary Completion Date
March 2014 (Actual)
Study Completion Date
March 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Otsuka Pharmaceutical Co., Ltd.

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Heart Failure
Keywords
Heart failure, Volume overload, Tolvaptan, loop diuretics

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
100 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Tolvaptan
Arm Type
Experimental
Arm Description
15 mg
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo
Intervention Type
Drug
Intervention Name(s)
Tolvaptan
Intervention Description
Once-daily oral administration of one tolvaptan 15 mg tablet in the morning
Intervention Type
Drug
Intervention Name(s)
Placebo of tolvaptan
Intervention Description
Once-daily oral administration of one placebo tablet in the morning
Primary Outcome Measure Information:
Title
Cummulative Incidence of Events at Week 26
Description
From start day of IMP administration to final day of follow up period, 1) and 2) below were defined as event Death from cardiovascular events 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
Title
Mortality （Number of Death）
Description
Statistical comparison was not done.
Time Frame
Week26
Title
Body Weight
Description
The comparison of the average of amount of change from baseline. Statistical comparison was not done.
Time Frame
Day15
Title
Number of Subjects Whose Lower Limb Edema Severity Grading Improved by One or More Grade
Description
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
Title
Jugular Venous Distension
Description
The comparison of the average of amount of change from baseline. Statistical comparison was not done.
Time Frame
Day15
Title
Change in Liver Size From Baseline
Description
The comparison of the average of amount of change from baseline. Statistical comparison was not done．
Time Frame
Day15
Title
Pulmonary Rales
Description
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
Title
Third Heart Sound
Description
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
Title
Cardiothoracic Ratio
Description
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
Title
Pulmonary Congestion
Description
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
Title
Plasma Brain Natriuretic Peptide (BNP) Concentration
Description
The comparison of the average of amount of change from baseline. Statistical comparison was not done.
Time Frame
Day15
Title
Dypnea
Description
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
Title
Number of Subjects Whose New York Heart Association (NYHA) Classification Improved by One More Grade From Baseline
Description
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
20 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Facility Information:
City
Chube Region
Country
Japan
City
Chushikoku Region
Country
Japan
City
Hokkaido Region
Country
Japan
City
Hokuriku Region
Country
Japan
City
Kansai Region
Country
Japan
City
Kanto Region
Country
Japan
City
Kyushu Region
Country
Japan
City
Tohoku Region
Country
Japan

12. IPD Sharing Statement

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Effect of Tolvaptan on Mid- to Long-term Prognosis of Heart Failure Patients

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