Trial Outcomes & Findings for Targeting Acute Congestion With Tolvaptan in Congestive Heart Failure (NCT NCT01644331)

NCT ID: NCT01644331

Last Updated: 2017-04-27

Results Overview

The number of patients with at least moderate improvement (as reported by patient) in dyspnea Likert scale at both 8 AND 24 hours AND without the need for escalation of therapy due to worsening heart failure (rescue therapy) or death within 24 hours.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 257 participants
• Primary outcome timeframe: 8 and 24 hours
• Results posted on: 2017-04-27

Participant Flow

Participant milestones

Measure	Tolvaptan IV furosemide (1 x oral dose given IV in Q12 hours divided doses or 40 mg IV Q12 hours, whichever is greater) plus oral Tolvaptan (given at 0, 12, 24 and 48 hours) Tolvaptan: Tolvaptan (given at 0, 12, 24 and 48 hours)	Placebo IV furosemide (1 x oral dose given IV Q12 divided doses or 40mg IV Q12 hours, whichever is greater) plus oral placebo (given at O, 24, 48 hours) Placebo: IV furosemide (1 x oral dose given IV in Q12 hours divided doses) plus oral placebo (given at 0, 12, 24 and 48 hours)
Overall Study STARTED	129	128
Overall Study COMPLETED	118	118
Overall Study NOT COMPLETED	11	10

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Targeting Acute Congestion With Tolvaptan in Congestive Heart Failure

Baseline characteristics by cohort

Measure	Tolvaptan n=129 Participants IV furosemide (1 x oral dose given IV in Q12 hours divided doses or 40 mg IV Q12 hours, whichever is greater) plus oral Tolvaptan (given at 0, 12, 24 and 48 hours) Tolvaptan: Tolvaptan (given at 0, 12, 24 and 48 hours)	Placebo n=128 Participants IV furosemide (1 x oral dose given IV Q12 divided doses or 40mg IV Q12 hours, whichever is greater) plus oral placebo (given at O, 24, 48 hours) Placebo: IV furosemide (1 x oral dose given IV in Q12 hours divided doses) plus oral placebo (given at 0, 12, 24 and 48 hours)	Total n=257 Participants Total of all reporting groups
Age, Continuous	66.42 years STANDARD_DEVIATION 12.9 • n=5 Participants	62.97 years STANDARD_DEVIATION 15.7 • n=7 Participants	64.70 years STANDARD_DEVIATION 14.4 • n=5 Participants
Sex: Female, Male Female	44 Participants n=5 Participants	42 Participants n=7 Participants	86 Participants n=5 Participants
Sex: Female, Male Male	85 Participants n=5 Participants	86 Participants n=7 Participants	171 Participants n=5 Participants
Region of Enrollment United States	129 Participants n=5 Participants	128 Participants n=7 Participants	257 Participants n=5 Participants

PRIMARY outcome

Timeframe: 8 and 24 hours

Population: Baseline population

The number of patients with at least moderate improvement (as reported by patient) in dyspnea Likert scale at both 8 AND 24 hours AND without the need for escalation of therapy due to worsening heart failure (rescue therapy) or death within 24 hours.

Outcome measures

Measure	Tolvaptan n=129 Participants IV furosemide (1 x oral dose given IV in Q12 hours divided doses or 40 mg IV Q12 hours, whichever is greater) plus oral Tolvaptan (given at 0, 12, 24 and 48 hours) Tolvaptan: Tolvaptan (given at 0, 12, 24 and 48 hours)	Placebo n=128 Participants IV furosemide (1 x oral dose given IV Q12 divided doses or 40mg IV Q12 hours, whichever is greater) plus oral placebo (given at O, 24, 48 hours) Placebo: IV furosemide (1 x oral dose given IV in Q12 hours divided doses) plus oral placebo (given at 0, 12, 24 and 48 hours)
Dyspnea Improvement Measured by Likert Scale at 8 and 24 Hours	20 Participants	26 Participants

SECONDARY outcome

Timeframe: 0, 24, 48 and 72 hours

Population: Baseline population

Change in Serum creatinine from baseline to 24, 48 and 72 hours

Outcome measures

Measure	Tolvaptan n=129 Participants IV furosemide (1 x oral dose given IV in Q12 hours divided doses or 40 mg IV Q12 hours, whichever is greater) plus oral Tolvaptan (given at 0, 12, 24 and 48 hours) Tolvaptan: Tolvaptan (given at 0, 12, 24 and 48 hours)	Placebo n=128 Participants IV furosemide (1 x oral dose given IV Q12 divided doses or 40mg IV Q12 hours, whichever is greater) plus oral placebo (given at O, 24, 48 hours) Placebo: IV furosemide (1 x oral dose given IV in Q12 hours divided doses) plus oral placebo (given at 0, 12, 24 and 48 hours)
Renal Function 24 hours	0.13 mg/dL Standard Deviation 0.4	0.04 mg/dL Standard Deviation 0.3
Renal Function 48 hours	0.10 mg/dL Standard Deviation 0.4	0.05 mg/dL Standard Deviation 0.4
Renal Function 72 hours	0.03 mg/dL Standard Deviation 0.6	0.06 mg/dL Standard Deviation 0.4

SECONDARY outcome

Timeframe: 0, 24, 48, and 72 hours

Population: Baseline population

Change in body weight from baseline to 24, 48, and 72 hours

Outcome measures

Measure	Tolvaptan n=129 Participants IV furosemide (1 x oral dose given IV in Q12 hours divided doses or 40 mg IV Q12 hours, whichever is greater) plus oral Tolvaptan (given at 0, 12, 24 and 48 hours) Tolvaptan: Tolvaptan (given at 0, 12, 24 and 48 hours)	Placebo n=128 Participants IV furosemide (1 x oral dose given IV Q12 divided doses or 40mg IV Q12 hours, whichever is greater) plus oral placebo (given at O, 24, 48 hours) Placebo: IV furosemide (1 x oral dose given IV in Q12 hours divided doses) plus oral placebo (given at 0, 12, 24 and 48 hours)
Weight Loss 24 hours	-4.41 lbs Standard Deviation 6.6	-1.16 lbs Standard Deviation 13.2
Weight Loss 48 hours	-6.11 lbs Standard Deviation 7.4	-3.46 lbs Standard Deviation 6.3
Weight Loss 72 hours	-8.19 lbs Standard Deviation 9.7	-5.53 lbs Standard Deviation 7.0

SECONDARY outcome

Timeframe: 0, 24, 48, and 72 hours

Population: baseline population

Change from baseline fluid balance at 24, 48, and 72 hours

Outcome measures

Measure	Tolvaptan n=129 Participants IV furosemide (1 x oral dose given IV in Q12 hours divided doses or 40 mg IV Q12 hours, whichever is greater) plus oral Tolvaptan (given at 0, 12, 24 and 48 hours) Tolvaptan: Tolvaptan (given at 0, 12, 24 and 48 hours)	Placebo n=128 Participants IV furosemide (1 x oral dose given IV Q12 divided doses or 40mg IV Q12 hours, whichever is greater) plus oral placebo (given at O, 24, 48 hours) Placebo: IV furosemide (1 x oral dose given IV in Q12 hours divided doses) plus oral placebo (given at 0, 12, 24 and 48 hours)
Fluid Loss 24 hours	-2182.25 mL Standard Deviation 1844.4	-1541.48 mL Standard Deviation 1524.5
Fluid Loss 48 hours	-1948.01 mL Standard Deviation 1635.6	-1419.09 mL Standard Deviation 1378.6
Fluid Loss 72 hours	-1757.09 mL Standard Deviation 1670.4	-1401.24 mL Standard Deviation 1386.5

SECONDARY outcome

Timeframe: 48 and 72 hours

Population: baseline population

Number of patients that experience moderate or greater improvement (patient reported) in dyspnea by 7 point Likert scale at 48 and 72 hours

Outcome measures

Measure	Tolvaptan n=129 Participants IV furosemide (1 x oral dose given IV in Q12 hours divided doses or 40 mg IV Q12 hours, whichever is greater) plus oral Tolvaptan (given at 0, 12, 24 and 48 hours) Tolvaptan: Tolvaptan (given at 0, 12, 24 and 48 hours)	Placebo n=128 Participants IV furosemide (1 x oral dose given IV Q12 divided doses or 40mg IV Q12 hours, whichever is greater) plus oral placebo (given at O, 24, 48 hours) Placebo: IV furosemide (1 x oral dose given IV in Q12 hours divided doses) plus oral placebo (given at 0, 12, 24 and 48 hours)
Dyspnea Likert 48 hours	88 Participants	74 Participants
Dyspnea Likert 72 hours	69 Participants	48 Participants

SECONDARY outcome

Timeframe: 7 days

Population: baseline population

Total days spent in hospital from baseline until discharge or death

Outcome measures

Measure	Tolvaptan n=129 Participants IV furosemide (1 x oral dose given IV in Q12 hours divided doses or 40 mg IV Q12 hours, whichever is greater) plus oral Tolvaptan (given at 0, 12, 24 and 48 hours) Tolvaptan: Tolvaptan (given at 0, 12, 24 and 48 hours)	Placebo n=128 Participants IV furosemide (1 x oral dose given IV Q12 divided doses or 40mg IV Q12 hours, whichever is greater) plus oral placebo (given at O, 24, 48 hours) Placebo: IV furosemide (1 x oral dose given IV in Q12 hours divided doses) plus oral placebo (given at 0, 12, 24 and 48 hours)
Hospital Stay	6.46 days Standard Deviation 5.9	7.35 days Standard Deviation 7.0

SECONDARY outcome

Timeframe: 72 hrs

Population: baseline population

Number of patients with worsening heart failure or death

Outcome measures

Measure	Tolvaptan n=129 Participants IV furosemide (1 x oral dose given IV in Q12 hours divided doses or 40 mg IV Q12 hours, whichever is greater) plus oral Tolvaptan (given at 0, 12, 24 and 48 hours) Tolvaptan: Tolvaptan (given at 0, 12, 24 and 48 hours)	Placebo n=128 Participants IV furosemide (1 x oral dose given IV Q12 divided doses or 40mg IV Q12 hours, whichever is greater) plus oral placebo (given at O, 24, 48 hours) Placebo: IV furosemide (1 x oral dose given IV in Q12 hours divided doses) plus oral placebo (given at 0, 12, 24 and 48 hours)
Worsening or Persistent Heart Failure or Death	54 Participants	60 Participants

SECONDARY outcome

Timeframe: 72 hours

Population: baseline population

clinical evidence of volume depletion requiring intervention other than holding diuretics during the 72 hours after randomization

Outcome measures

Measure	Tolvaptan n=129 Participants IV furosemide (1 x oral dose given IV in Q12 hours divided doses or 40 mg IV Q12 hours, whichever is greater) plus oral Tolvaptan (given at 0, 12, 24 and 48 hours) Tolvaptan: Tolvaptan (given at 0, 12, 24 and 48 hours)	Placebo n=128 Participants IV furosemide (1 x oral dose given IV Q12 divided doses or 40mg IV Q12 hours, whichever is greater) plus oral placebo (given at O, 24, 48 hours) Placebo: IV furosemide (1 x oral dose given IV in Q12 hours divided doses) plus oral placebo (given at 0, 12, 24 and 48 hours)
Over-diuresis	7 Participants	3 Participants

SECONDARY outcome

Timeframe: 0, 24, 48, and 72 hours

Population: baseline population

Change in serum sodium from baseline to 24, 48, and 72 hours

Outcome measures

Measure	Tolvaptan n=129 Participants IV furosemide (1 x oral dose given IV in Q12 hours divided doses or 40 mg IV Q12 hours, whichever is greater) plus oral Tolvaptan (given at 0, 12, 24 and 48 hours) Tolvaptan: Tolvaptan (given at 0, 12, 24 and 48 hours)	Placebo n=128 Participants IV furosemide (1 x oral dose given IV Q12 divided doses or 40mg IV Q12 hours, whichever is greater) plus oral placebo (given at O, 24, 48 hours) Placebo: IV furosemide (1 x oral dose given IV in Q12 hours divided doses) plus oral placebo (given at 0, 12, 24 and 48 hours)
Serum Sodium 24 hours	3.18 mmol/L Standard Deviation 3.3	0.23 mmol/L Standard Deviation 2.5
Serum Sodium 48 hours	3.34 mmol/L Standard Deviation 3.7	-0.24 mmol/L Standard Deviation 2.8
Serum Sodium 72 hours	2.84 mmol/L Standard Deviation 3.9	-0.44 mmol/L Standard Deviation 2.9

SECONDARY outcome

Timeframe: 0, 24, 48, and 72 hours

Population: baseline population

Change in NRS for assessment of dyspnea from baseline to 24, 48, and 72 hours (scale ranges from 0-No difficulty breathing to 10-Difficulty as bad as you can imagine)

Outcome measures

Measure	Tolvaptan n=129 Participants IV furosemide (1 x oral dose given IV in Q12 hours divided doses or 40 mg IV Q12 hours, whichever is greater) plus oral Tolvaptan (given at 0, 12, 24 and 48 hours) Tolvaptan: Tolvaptan (given at 0, 12, 24 and 48 hours)	Placebo n=128 Participants IV furosemide (1 x oral dose given IV Q12 divided doses or 40mg IV Q12 hours, whichever is greater) plus oral placebo (given at O, 24, 48 hours) Placebo: IV furosemide (1 x oral dose given IV in Q12 hours divided doses) plus oral placebo (given at 0, 12, 24 and 48 hours)
Dyspnea 11 Point NRS 24 hours	-2.20 units on a scale Standard Deviation 2.5	-1.84 units on a scale Standard Deviation 2.1
Dyspnea 11 Point NRS 48 hours	-2.85 units on a scale Standard Deviation 2.7	-2.29 units on a scale Standard Deviation 2.3
Dyspnea 11 Point NRS 72 hours	-3.07 units on a scale Standard Deviation 3.0	-2.42 units on a scale Standard Deviation 2.4

SECONDARY outcome

Timeframe: 24, 48, and 72 hours

Population: baseline population

Jugular Venous Pressure (JVP) < 8 cm, no orthopnea, trace peripheral edema or less, and will be assessed at 24, 48, and 72 hours

Outcome measures

Measure	Tolvaptan n=129 Participants IV furosemide (1 x oral dose given IV in Q12 hours divided doses or 40 mg IV Q12 hours, whichever is greater) plus oral Tolvaptan (given at 0, 12, 24 and 48 hours) Tolvaptan: Tolvaptan (given at 0, 12, 24 and 48 hours)	Placebo n=128 Participants IV furosemide (1 x oral dose given IV Q12 divided doses or 40mg IV Q12 hours, whichever is greater) plus oral placebo (given at O, 24, 48 hours) Placebo: IV furosemide (1 x oral dose given IV in Q12 hours divided doses) plus oral placebo (given at 0, 12, 24 and 48 hours)
Freedom From Congestion 24 hours	9 Participants	12 Participants
Freedom From Congestion 48 hours	24 Participants	20 Participants
Freedom From Congestion 72 hours	27 Participants	17 Participants

SECONDARY outcome

Timeframe: 72 hours

Population: baseline population

increase in serum creatinine ≥ 0.3mg/dl from randomization at any time point during 72 hours after randomization

Outcome measures

Measure	Tolvaptan n=129 Participants IV furosemide (1 x oral dose given IV in Q12 hours divided doses or 40 mg IV Q12 hours, whichever is greater) plus oral Tolvaptan (given at 0, 12, 24 and 48 hours) Tolvaptan: Tolvaptan (given at 0, 12, 24 and 48 hours)	Placebo n=128 Participants IV furosemide (1 x oral dose given IV Q12 divided doses or 40mg IV Q12 hours, whichever is greater) plus oral placebo (given at O, 24, 48 hours) Placebo: IV furosemide (1 x oral dose given IV in Q12 hours divided doses) plus oral placebo (given at 0, 12, 24 and 48 hours)
Development of Worsening Renal Function	50 Participants	34 Participants

SECONDARY outcome

Timeframe: 30 days

Population: baseline population

Total days hospitalized or deceased during the 30 days after randomization

Outcome measures

Measure	Tolvaptan n=129 Participants IV furosemide (1 x oral dose given IV in Q12 hours divided doses or 40 mg IV Q12 hours, whichever is greater) plus oral Tolvaptan (given at 0, 12, 24 and 48 hours) Tolvaptan: Tolvaptan (given at 0, 12, 24 and 48 hours)	Placebo n=128 Participants IV furosemide (1 x oral dose given IV Q12 divided doses or 40mg IV Q12 hours, whichever is greater) plus oral placebo (given at O, 24, 48 hours) Placebo: IV furosemide (1 x oral dose given IV in Q12 hours divided doses) plus oral placebo (given at 0, 12, 24 and 48 hours)
Days Hospitalized or Deceased	10.19 days Standard Deviation 10.9	11.69 days Standard Deviation 11.7

SECONDARY outcome

Timeframe: 30 days

Population: baseline population

All cause death or rehospitalization (to include unscheduled clinic visits or ED visits) at 30 days (Kaplan-Meier and 95% confidence interval)

Outcome measures

Measure	Tolvaptan n=129 Participants IV furosemide (1 x oral dose given IV in Q12 hours divided doses or 40 mg IV Q12 hours, whichever is greater) plus oral Tolvaptan (given at 0, 12, 24 and 48 hours) Tolvaptan: Tolvaptan (given at 0, 12, 24 and 48 hours)	Placebo n=128 Participants IV furosemide (1 x oral dose given IV Q12 divided doses or 40mg IV Q12 hours, whichever is greater) plus oral placebo (given at O, 24, 48 hours) Placebo: IV furosemide (1 x oral dose given IV in Q12 hours divided doses) plus oral placebo (given at 0, 12, 24 and 48 hours)
All Cause Death or Rehospitalization	0.33 proportion of participants Interval 0.25 to 0.42	0.29 proportion of participants Interval 0.22 to 0.38

Adverse Events

Tolvaptan

Serious events: 8 serious events

Other events: 101 other events

Deaths: 0 deaths

Placebo

Serious events: 2 serious events

Other events: 107 other events

Deaths: 0 deaths

Serious adverse events

Measure	Tolvaptan n=129 participants at risk IV furosemide (1 x oral dose given IV in Q12 hours divided doses or 40 mg IV Q12 hours, whichever is greater) plus oral Tolvaptan (given at 0, 12, 24 and 48 hours) Tolvaptan: Tolvaptan (given at 0, 12, 24 and 48 hours)	Placebo n=128 participants at risk IV furosemide (1 x oral dose given IV Q12 divided doses or 40mg IV Q12 hours, whichever is greater) plus oral placebo (given at O, 24, 48 hours) Placebo: IV furosemide (1 x oral dose given IV in Q12 hours divided doses) plus oral placebo (given at 0, 12, 24 and 48 hours)
Renal and urinary disorders Blood Sodium Increase	0.78% 1/129 • Number of events 1 • Serious adverse events occurring from randomization through day 7 or discharge (whichever occurred first)	0.00% 0/128 • Serious adverse events occurring from randomization through day 7 or discharge (whichever occurred first)
Blood and lymphatic system disorders Epistaxis	0.78% 1/129 • Number of events 1 • Serious adverse events occurring from randomization through day 7 or discharge (whichever occurred first)	0.00% 0/128 • Serious adverse events occurring from randomization through day 7 or discharge (whichever occurred first)
Vascular disorders Cerebrovascular Accident	0.78% 1/129 • Number of events 1 • Serious adverse events occurring from randomization through day 7 or discharge (whichever occurred first)	0.78% 1/128 • Number of events 1 • Serious adverse events occurring from randomization through day 7 or discharge (whichever occurred first)
Cardiac disorders Hypotension	0.78% 1/129 • Number of events 1 • Serious adverse events occurring from randomization through day 7 or discharge (whichever occurred first)	0.00% 0/128 • Serious adverse events occurring from randomization through day 7 or discharge (whichever occurred first)
Cardiac disorders Cardiogenic Shock	0.78% 1/129 • Number of events 1 • Serious adverse events occurring from randomization through day 7 or discharge (whichever occurred first)	0.00% 0/128 • Serious adverse events occurring from randomization through day 7 or discharge (whichever occurred first)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Uterine Cancer	0.78% 1/129 • Number of events 1 • Serious adverse events occurring from randomization through day 7 or discharge (whichever occurred first)	0.00% 0/128 • Serious adverse events occurring from randomization through day 7 or discharge (whichever occurred first)
Respiratory, thoracic and mediastinal disorders Chronic Obstructive Pulmonary Disease	0.00% 0/129 • Serious adverse events occurring from randomization through day 7 or discharge (whichever occurred first)	0.78% 1/128 • Number of events 1 • Serious adverse events occurring from randomization through day 7 or discharge (whichever occurred first)
Infections and infestations Sepsis	0.78% 1/129 • Number of events 1 • Serious adverse events occurring from randomization through day 7 or discharge (whichever occurred first)	0.00% 0/128 • Serious adverse events occurring from randomization through day 7 or discharge (whichever occurred first)
Renal and urinary disorders Hyponatraemia	0.78% 1/129 • Number of events 1 • Serious adverse events occurring from randomization through day 7 or discharge (whichever occurred first)	0.00% 0/128 • Serious adverse events occurring from randomization through day 7 or discharge (whichever occurred first)

Other adverse events

Measure	Tolvaptan n=129 participants at risk IV furosemide (1 x oral dose given IV in Q12 hours divided doses or 40 mg IV Q12 hours, whichever is greater) plus oral Tolvaptan (given at 0, 12, 24 and 48 hours) Tolvaptan: Tolvaptan (given at 0, 12, 24 and 48 hours)	Placebo n=128 participants at risk IV furosemide (1 x oral dose given IV Q12 divided doses or 40mg IV Q12 hours, whichever is greater) plus oral placebo (given at O, 24, 48 hours) Placebo: IV furosemide (1 x oral dose given IV in Q12 hours divided doses) plus oral placebo (given at 0, 12, 24 and 48 hours)
Cardiac disorders Atrial Fibrillation	10.1% 13/129 • Number of events 13 • Serious adverse events occurring from randomization through day 7 or discharge (whichever occurred first)	14.8% 19/128 • Number of events 19 • Serious adverse events occurring from randomization through day 7 or discharge (whichever occurred first)
Cardiac disorders Ventricular Tachycardia	3.9% 5/129 • Number of events 5 • Serious adverse events occurring from randomization through day 7 or discharge (whichever occurred first)	5.5% 7/128 • Number of events 7 • Serious adverse events occurring from randomization through day 7 or discharge (whichever occurred first)
Cardiac disorders Myocardial Infarction	0.78% 1/129 • Number of events 1 • Serious adverse events occurring from randomization through day 7 or discharge (whichever occurred first)	0.00% 0/128 • Serious adverse events occurring from randomization through day 7 or discharge (whichever occurred first)
Cardiac disorders Acute Coronary Syndrome	0.78% 1/129 • Number of events 1 • Serious adverse events occurring from randomization through day 7 or discharge (whichever occurred first)	0.00% 0/128 • Serious adverse events occurring from randomization through day 7 or discharge (whichever occurred first)
Renal and urinary disorders Acute Renal Failure	18.6% 24/129 • Number of events 24 • Serious adverse events occurring from randomization through day 7 or discharge (whichever occurred first)	11.7% 15/128 • Number of events 15 • Serious adverse events occurring from randomization through day 7 or discharge (whichever occurred first)
Cardiac disorders Worsening Heart Failure	38.0% 49/129 • Number of events 86 • Serious adverse events occurring from randomization through day 7 or discharge (whichever occurred first)	46.1% 59/128 • Number of events 106 • Serious adverse events occurring from randomization through day 7 or discharge (whichever occurred first)
Cardiac disorders Death	6.2% 8/129 • Number of events 8 • Serious adverse events occurring from randomization through day 7 or discharge (whichever occurred first)	5.5% 7/128 • Number of events 7 • Serious adverse events occurring from randomization through day 7 or discharge (whichever occurred first)

Additional Information

G. Michael Felker, MD

Duke Clinical Research Institute

Phone: 919-668-8919

Email: Michael.Felker@duke.edu

Results disclosure agreements

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

Restriction type: GT60