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

• Sponsor: Otsuka Pharmaceutical Co., Ltd. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01439009
• Collaborator: (none)
• Enrollment: 100
• Locations: 8
• Arms: 2
• Duration (Months): 30
• Patients Per Site: 12.5
• Patients Per Site Per Month: 0.4

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Heart Failure	Drug: Tolvaptan; Drug: Placebo of tolvaptan	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 100 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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 Start Date: Sep 1, 2011
• Actual Primary Completion Date: Mar 1, 2014
• Actual Study Completion Date: Mar 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tolvaptan 15 mg	Drug: Tolvaptan; Once-daily oral administration of one tolvaptan 15 mg tablet in the morning
Placebo Comparator: Placebo Placebo	Drug: Placebo of tolvaptan; Once-daily oral administration of one placebo tablet in the morning

Outcome Measures

Primary Outcome Measures

1. 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 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)

2. Mortality （Number of Death） [Week26]

   Statistical comparison was not done.

3. Body Weight [Day15]

   The comparison of the average of amount of change from baseline. Statistical comparison was not done.

4. 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.

5. Jugular Venous Distension [Day15]

   The comparison of the average of amount of change from baseline. Statistical comparison was not done.

6. Change in Liver Size From Baseline [Day15]

   The comparison of the average of amount of change from baseline. Statistical comparison was not done．

7. 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.

8. 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.

9. 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.

10. 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.

11. Plasma Brain Natriuretic Peptide (BNP) Concentration [Day15]

    The comparison of the average of amount of change from baseline. Statistical comparison was not done.

12. 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.

13. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Chube Region		Japan
2		Chushikoku Region		Japan
3		Hokkaido Region		Japan
4		Hokuriku Region		Japan
5		Kansai Region		Japan
6		Kanto Region		Japan
7		Kyushu Region		Japan
8		Tohoku Region		Japan

Sponsors and Collaborators

• Otsuka Pharmaceutical Co., Ltd.

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Otsuka Pharmaceutical Co., Ltd.
• ClinicalTrials.gov Identifier: NCT01439009
• Other Study ID Numbers: 156-10-005; JapicCTI-111621
• First Posted: Sep 22, 2011
• Last Update Posted: Oct 22, 2019
• Last Verified: Oct 1, 2019

• Keywords provided by Otsuka Pharmaceutical Co., Ltd.: Heart failure; Volume overload; Tolvaptan; loop diuretics
• Additional relevant MeSH terms: Heart Failure; Tolvaptan

Study Results

Participant Flow

Arm/Group Title	Tolvaptan	Placebo
Arm/Group Description	15 mg Tolvaptan: Once-daily oral administration of one tolvaptan 15 mg tablet in the morning	Placebo Placebo of tolvaptan: Once-daily oral administration of one placebo tablet in the morning
Period Title: Overall Study
STARTED	50	50
COMPLETED	42	47
NOT COMPLETED	8	3

Baseline Characteristics

Arm/Group Title	Tolvaptan	Placebo	Total
Arm/Group Description	15 mg Tolvaptan: Once-daily oral administration of one tolvaptan 15 mg tablet in the morning	Placebo Placebo of tolvaptan: Once-daily oral administration of one placebo tablet in the morning	Total of all reporting groups
Overall Participants	50	50	100
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	9 18%	13 26%	22 22%
>=65 years	41 82%	37 74%	78 78%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	73.8 (8.4)	71.7 (11.2)	72.8 (9.9)
Sex: Female, Male (Count of Participants)
Female	21 42%	13 26%	34 34%
Male	29 58%	37 74%	66 66%
Region of Enrollment (participants) [Number]
Japan	50 100%	50 100%	100 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tolvaptan	Placebo
Arm/Group Description	15 mg Tolvaptan: Once-daily oral administration of one tolvaptan 15 mg tablet in the morning	Placebo Placebo of tolvaptan: Once-daily oral administration of one placebo tablet in the morning
Measure Participants	50	50
Number [Percentage of events at 26 weeks]	35.6	43.8

2. Primary Outcome

Title	Mortality （Number of Death）
Description	Statistical comparison was not done.
Time Frame	Week26

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tolvaptan	Placebo
Arm/Group Description	15 mg Tolvaptan: Once-daily oral administration of one tolvaptan 15 mg tablet in the morning	Placebo Placebo of tolvaptan: Once-daily oral administration of one placebo tablet in the morning
Measure Participants	50	50
Number [participants]	2 4%	3 6%

3. Primary Outcome

Title	Body Weight
Description	The comparison of the average of amount of change from baseline. Statistical comparison was not done.
Time Frame	Day15

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tolvaptan	Placebo
Arm/Group Description	15 mg Tolvaptan: Once-daily oral administration of one tolvaptan 15 mg tablet in the morning	Placebo Placebo of tolvaptan: Once-daily oral administration of one placebo tablet in the morning
Measure Participants	47	44
Mean (Standard Deviation) [kg]	-1.99 (1.61)	-1.20 (1.97)

4. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tolvaptan	Placebo
Arm/Group Description	15 mg Tolvaptan: Once-daily oral administration of one tolvaptan 15 mg tablet in the morning	Placebo Placebo of tolvaptan: Once-daily oral administration of one placebo tablet in the morning
Measure Participants	35	25
Number [participants]	27 54%	16 32%

5. Primary Outcome

Title	Jugular Venous Distension
Description	The comparison of the average of amount of change from baseline. Statistical comparison was not done.
Time Frame	Day15

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tolvaptan	Placebo
Arm/Group Description	15 mg Tolvaptan: Once-daily oral administration of one tolvaptan 15 mg tablet in the morning	Placebo Placebo of tolvaptan: Once-daily oral administration of one placebo tablet in the morning
Measure Participants	47	43
Mean (Standard Deviation) [cm]	-0.94 (2.07)	-1.23 (2.78)

6. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tolvaptan	Placebo
Arm/Group Description	15 mg Tolvaptan: Once-daily oral administration of one tolvaptan 15 mg tablet in the morning	Placebo Placebo of tolvaptan: Once-daily oral administration of one placebo tablet in the morning
Measure Participants	47	43
Mean (Standard Deviation) [cm]	-0.20 (0.52)	-0.19 (0.55)

7. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tolvaptan	Placebo
Arm/Group Description	15 mg Tolvaptan: Once-daily oral administration of one tolvaptan 15 mg tablet in the morning	Placebo Placebo of tolvaptan: Once-daily oral administration of one placebo tablet in the morning
Measure Participants	16	17
Number [participants]	13 26%	9 18%

8. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tolvaptan	Placebo
Arm/Group Description	15 mg Tolvaptan: Once-daily oral administration of one tolvaptan 15 mg tablet in the morning	Placebo Placebo of tolvaptan: Once-daily oral administration of one placebo tablet in the morning
Measure Participants	14	16
Number [participants]	8 16%	10 20%

9. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tolvaptan	Placebo
Arm/Group Description	15 mg Tolvaptan: Once-daily oral administration of one tolvaptan 15 mg tablet in the morning	Placebo Placebo of tolvaptan: Once-daily oral administration of one placebo tablet in the morning
Measure Participants	47	44
Mean (Standard Deviation) [Percentage]	-2.13 (3.53)	-0.83 (3.85)

10. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tolvaptan	Placebo
Arm/Group Description	15 mg Tolvaptan: Once-daily oral administration of one tolvaptan 15 mg tablet in the morning	Placebo Placebo of tolvaptan: Once-daily oral administration of one placebo tablet in the morning
Measure Participants	40	42
Number [participants]	24 48%	20 40%

11. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tolvaptan	Placebo
Arm/Group Description	15 mg Tolvaptan: Once-daily oral administration of one tolvaptan 15 mg tablet in the morning	Placebo Placebo of tolvaptan: Once-daily oral administration of one placebo tablet in the morning
Measure Participants	46	44
Mean (Standard Deviation) [pg/mL]	-72.60 (268.90)	-166.96 (353.34)

12. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tolvaptan	Placebo
Arm/Group Description	15 mg Tolvaptan: Once-daily oral administration of one tolvaptan 15 mg tablet in the morning	Placebo Placebo of tolvaptan: Once-daily oral administration of one placebo tablet in the morning
Measure Participants	15	20
Number [participants]	11 22%	12 24%

13. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tolvaptan	Placebo
Arm/Group Description	15 mg Tolvaptan: Once-daily oral administration of one tolvaptan 15 mg tablet in the morning	Placebo Placebo of tolvaptan: Once-daily oral administration of one placebo tablet in the morning
Measure Participants	47	44
Number [participants]	22 44%	24 48%

Adverse Events

Time Frame	26 weeks
Arm/Group Title	Tolvaptan		Placebo
Arm/Group Description	15 mg Tolvaptan: Once-daily oral administration of one tolvaptan 15 mg tablet in the morning		Placebo Placebo of tolvaptan: Once-daily oral administration of one placebo tablet in the morning
All Cause Mortality
	Tolvaptan		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Tolvaptan		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	24/50 (48%)		22/50 (44%)
Cardiac disorders
Cardiac failure	13/50 (26%)		19/50 (38%)
Acute Cardiac Failure	0/50 (0%)		1/50 (2%)
Congestive Cardiac Failure	1/50 (2%)		0/50 (0%)
Ventricular Tachycardia	0/50 (0%)		1/50 (2%)
Eye disorders
Cataract	1/50 (2%)		0/50 (0%)
Diabetic retina edema	1/50 (2%)		0/50 (0%)
Gastrointestinal disorders
Inguinal hernia	1/50 (2%)		0/50 (0%)
Nausea	1/50 (2%)		0/50 (0%)
Large intestine polyp	1/50 (2%)		0/50 (0%)
General disorders
Fever	1/50 (2%)		0/50 (0%)
Infections and infestations
Rhinopharyngitis	0/50 (0%)		1/50 (2%)
Pneumoria	0/50 (0%)		1/50 (2%)
Investigations
C-reactive protein increased	1/50 (2%)		0/50 (0%)
Occult blood positive	1/50 (2%)		0/50 (0%)
Musculoskeletal and connective tissue disorders
Osteoarthritis	1/50 (2%)		0/50 (0%)
Nervous system disorders
Embolic stroke	1/50 (2%)		0/50 (0%)
Loss of consciousness	0/50 (0%)		1/50 (2%)
Renal and urinary disorders
Renal failure acute	1/50 (2%)		0/50 (0%)
Renal failure chronic	0/50 (0%)		1/50 (2%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	1/50 (2%)		0/50 (0%)
Other (Not Including Serious) Adverse Events
	Tolvaptan		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	31/50 (62%)		7/50 (14%)
Gastrointestinal disorders
Constipation	6/50 (12%)		2/50 (4%)
General disorders
Thirst	10/50 (20%)		1/50 (2%)
Injury, poisoning and procedural complications
Contusion	1/50 (2%)		3/50 (6%)
Investigations
Blood potassium increased	3/50 (6%)		1/50 (2%)
Blood sodium increased	8/50 (16%)		0/50 (0%)
Metabolism and nutrition disorders
Hypokalaemia	3/50 (6%)		0/50 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.