Trial Outcomes & Findings for Effect of Tolvaptan on Mid- to Long-term Prognosis of Heart Failure Patients (NCT NCT01439009)

NCT ID: NCT01439009

Last Updated: 2019-10-22

Results Overview

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)

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 100 participants
• Primary outcome timeframe: Week 26
• Results posted on: 2019-10-22

Participant Flow

Participant milestones

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

Reasons for withdrawal

Measure	Tolvaptan 15 mg Tolvaptan: Once-daily oral administration of one tolvaptan 15 mg tablet in the morning	Placebo Placebo Placebo of tolvaptan: Once-daily oral administration of one placebo tablet in the morning
Overall Study Physician Decision	5	3
Overall Study Protocol Violation	2	0
Overall Study Deviation of exclusion criteria	1	0

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Tolvaptan n=50 Participants 15 mg Tolvaptan: Once-daily oral administration of one tolvaptan 15 mg tablet in the morning	Placebo n=50 Participants Placebo Placebo of tolvaptan: Once-daily oral administration of one placebo tablet in the morning	Total n=100 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	9 Participants n=5 Participants	13 Participants n=7 Participants	22 Participants n=5 Participants
Age, Categorical >=65 years	41 Participants n=5 Participants	37 Participants n=7 Participants	78 Participants n=5 Participants
Age, Continuous	73.8 years STANDARD_DEVIATION 8.4 • n=5 Participants	71.7 years STANDARD_DEVIATION 11.2 • n=7 Participants	72.8 years STANDARD_DEVIATION 9.9 • n=5 Participants
Sex: Female, Male Female	21 Participants n=5 Participants	13 Participants n=7 Participants	34 Participants n=5 Participants
Sex: Female, Male Male	29 Participants n=5 Participants	37 Participants n=7 Participants	66 Participants n=5 Participants
Region of Enrollment Japan	50 participants n=5 Participants	50 participants n=7 Participants	100 participants n=5 Participants

PRIMARY outcome

Timeframe: 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)

Outcome measures

Measure	Tolvaptan n=50 Participants 15 mg Tolvaptan: Once-daily oral administration of one tolvaptan 15 mg tablet in the morning	Placebo n=50 Participants Placebo Placebo of tolvaptan: Once-daily oral administration of one placebo tablet in the morning
Cummulative Incidence of Events at Week 26	35.6 Percentage of events at 26 weeks	43.8 Percentage of events at 26 weeks

PRIMARY outcome

Timeframe: Week26

Statistical comparison was not done.

Outcome measures

Measure	Tolvaptan n=50 Participants 15 mg Tolvaptan: Once-daily oral administration of one tolvaptan 15 mg tablet in the morning	Placebo n=50 Participants Placebo Placebo of tolvaptan: Once-daily oral administration of one placebo tablet in the morning
Mortality （Number of Death）	2 participants	3 participants

PRIMARY outcome

Timeframe: Day15

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

Outcome measures

Measure	Tolvaptan n=47 Participants 15 mg Tolvaptan: Once-daily oral administration of one tolvaptan 15 mg tablet in the morning	Placebo n=44 Participants Placebo Placebo of tolvaptan: Once-daily oral administration of one placebo tablet in the morning
Body Weight	-1.99 kg Standard Deviation 1.61	-1.20 kg Standard Deviation 1.97

PRIMARY outcome

Timeframe: 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.

Outcome measures

Measure	Tolvaptan n=35 Participants 15 mg Tolvaptan: Once-daily oral administration of one tolvaptan 15 mg tablet in the morning	Placebo n=25 Participants Placebo Placebo of tolvaptan: Once-daily oral administration of one placebo tablet in the morning
Number of Subjects Whose Lower Limb Edema Severity Grading Improved by One or More Grade	27 participants	16 participants

PRIMARY outcome

Timeframe: Day15

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

Outcome measures

Measure	Tolvaptan n=47 Participants 15 mg Tolvaptan: Once-daily oral administration of one tolvaptan 15 mg tablet in the morning	Placebo n=43 Participants Placebo Placebo of tolvaptan: Once-daily oral administration of one placebo tablet in the morning
Jugular Venous Distension	-0.94 cm Standard Deviation 2.07	-1.23 cm Standard Deviation 2.78

PRIMARY outcome

Timeframe: Day15

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

Outcome measures

Measure	Tolvaptan n=47 Participants 15 mg Tolvaptan: Once-daily oral administration of one tolvaptan 15 mg tablet in the morning	Placebo n=43 Participants Placebo Placebo of tolvaptan: Once-daily oral administration of one placebo tablet in the morning
Change in Liver Size From Baseline	-0.20 cm Standard Deviation 0.52	-0.19 cm Standard Deviation 0.55

PRIMARY outcome

Timeframe: 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.

Outcome measures

Measure	Tolvaptan n=16 Participants 15 mg Tolvaptan: Once-daily oral administration of one tolvaptan 15 mg tablet in the morning	Placebo n=17 Participants Placebo Placebo of tolvaptan: Once-daily oral administration of one placebo tablet in the morning
Pulmonary Rales	13 participants	9 participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Measure	Tolvaptan n=14 Participants 15 mg Tolvaptan: Once-daily oral administration of one tolvaptan 15 mg tablet in the morning	Placebo n=16 Participants Placebo Placebo of tolvaptan: Once-daily oral administration of one placebo tablet in the morning
Third Heart Sound	8 participants	10 participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Measure	Tolvaptan n=47 Participants 15 mg Tolvaptan: Once-daily oral administration of one tolvaptan 15 mg tablet in the morning	Placebo n=44 Participants Placebo Placebo of tolvaptan: Once-daily oral administration of one placebo tablet in the morning
Cardiothoracic Ratio	-2.13 Percentage Standard Deviation 3.53	-0.83 Percentage Standard Deviation 3.85

PRIMARY outcome

Timeframe: 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.

Outcome measures

Measure	Tolvaptan n=40 Participants 15 mg Tolvaptan: Once-daily oral administration of one tolvaptan 15 mg tablet in the morning	Placebo n=42 Participants Placebo Placebo of tolvaptan: Once-daily oral administration of one placebo tablet in the morning
Pulmonary Congestion	24 participants	20 participants

PRIMARY outcome

Timeframe: Day15

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

Outcome measures

Measure	Tolvaptan n=46 Participants 15 mg Tolvaptan: Once-daily oral administration of one tolvaptan 15 mg tablet in the morning	Placebo n=44 Participants Placebo Placebo of tolvaptan: Once-daily oral administration of one placebo tablet in the morning
Plasma Brain Natriuretic Peptide (BNP) Concentration	-72.60 pg/mL Standard Deviation 268.90	-166.96 pg/mL Standard Deviation 353.34

PRIMARY outcome

Timeframe: 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.

Outcome measures

Measure	Tolvaptan n=15 Participants 15 mg Tolvaptan: Once-daily oral administration of one tolvaptan 15 mg tablet in the morning	Placebo n=20 Participants Placebo Placebo of tolvaptan: Once-daily oral administration of one placebo tablet in the morning
Dypnea	11 participants	12 participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Measure	Tolvaptan n=47 Participants 15 mg Tolvaptan: Once-daily oral administration of one tolvaptan 15 mg tablet in the morning	Placebo n=44 Participants Placebo Placebo of tolvaptan: Once-daily oral administration of one placebo tablet in the morning
Number of Subjects Whose New York Heart Association (NYHA) Classification Improved by One More Grade From Baseline	22 participants	24 participants

Adverse Events

Tolvaptan

Serious events: 24 serious events

Other events: 31 other events

Deaths: 0 deaths

Placebo

Serious events: 22 serious events

Other events: 7 other events

Deaths: 0 deaths

Serious adverse events

Measure	Tolvaptan n=50 participants at risk 15 mg Tolvaptan: Once-daily oral administration of one tolvaptan 15 mg tablet in the morning	Placebo n=50 participants at risk Placebo Placebo of tolvaptan: Once-daily oral administration of one placebo tablet in the morning
Cardiac disorders Cardiac failure	26.0% 13/50 • 26 weeks	38.0% 19/50 • 26 weeks
Cardiac disorders Acute Cardiac Failure	0.00% 0/50 • 26 weeks	2.0% 1/50 • 26 weeks
Cardiac disorders Congestive Cardiac Failure	2.0% 1/50 • 26 weeks	0.00% 0/50 • 26 weeks
Cardiac disorders Ventricular Tachycardia	0.00% 0/50 • 26 weeks	2.0% 1/50 • 26 weeks
Eye disorders Cataract	2.0% 1/50 • 26 weeks	0.00% 0/50 • 26 weeks
Eye disorders Diabetic retina edema	2.0% 1/50 • 26 weeks	0.00% 0/50 • 26 weeks
Gastrointestinal disorders Inguinal hernia	2.0% 1/50 • 26 weeks	0.00% 0/50 • 26 weeks
Gastrointestinal disorders Nausea	2.0% 1/50 • 26 weeks	0.00% 0/50 • 26 weeks
Gastrointestinal disorders Large intestine polyp	2.0% 1/50 • 26 weeks	0.00% 0/50 • 26 weeks
General disorders Fever	2.0% 1/50 • 26 weeks	0.00% 0/50 • 26 weeks
Infections and infestations Rhinopharyngitis	0.00% 0/50 • 26 weeks	2.0% 1/50 • 26 weeks
Infections and infestations Pneumoria	0.00% 0/50 • 26 weeks	2.0% 1/50 • 26 weeks
Investigations C-reactive protein increased	2.0% 1/50 • 26 weeks	0.00% 0/50 • 26 weeks
Investigations Occult blood positive	2.0% 1/50 • 26 weeks	0.00% 0/50 • 26 weeks
Musculoskeletal and connective tissue disorders Osteoarthritis	2.0% 1/50 • 26 weeks	0.00% 0/50 • 26 weeks
Nervous system disorders Embolic stroke	2.0% 1/50 • 26 weeks	0.00% 0/50 • 26 weeks
Nervous system disorders Loss of consciousness	0.00% 0/50 • 26 weeks	2.0% 1/50 • 26 weeks
Renal and urinary disorders Renal failure acute	2.0% 1/50 • 26 weeks	0.00% 0/50 • 26 weeks
Renal and urinary disorders Renal failure chronic	0.00% 0/50 • 26 weeks	2.0% 1/50 • 26 weeks
Respiratory, thoracic and mediastinal disorders Epistaxis	2.0% 1/50 • 26 weeks	0.00% 0/50 • 26 weeks

Other adverse events

Measure	Tolvaptan n=50 participants at risk 15 mg Tolvaptan: Once-daily oral administration of one tolvaptan 15 mg tablet in the morning	Placebo n=50 participants at risk Placebo Placebo of tolvaptan: Once-daily oral administration of one placebo tablet in the morning
Gastrointestinal disorders Constipation	12.0% 6/50 • 26 weeks	4.0% 2/50 • 26 weeks
General disorders Thirst	20.0% 10/50 • 26 weeks	2.0% 1/50 • 26 weeks
Injury, poisoning and procedural complications Contusion	2.0% 1/50 • 26 weeks	6.0% 3/50 • 26 weeks
Investigations Blood potassium increased	6.0% 3/50 • 26 weeks	2.0% 1/50 • 26 weeks
Investigations Blood sodium increased	16.0% 8/50 • 26 weeks	0.00% 0/50 • 26 weeks
Metabolism and nutrition disorders Hypokalaemia	6.0% 3/50 • 26 weeks	0.00% 0/50 • 26 weeks

Additional Information

Director of Clinical Research and Development

Otsuka Pharmaceutical Co., Ltd

Phone: +81-3-6361-7366

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place