AQUA-AHF: Aquaresis Utility for Hyponatremic Acute Heart Failure Study

• Sponsor: University of Southern California (Other)
• Overall Status: Completed
• CT.gov ID: NCT02183792
• Collaborator: Otsuka America Pharmaceutical (Industry)
• Enrollment: 33
• Locations: 2
• Arms: 2
• Duration (Months): 39
• Patients Per Site: 16.5
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

Hyponatremia is a common finding in acute heart failure (HF) patients and is associated with worse prognosis. In addition to its prognostic value, hyponatremia may have importance during the acute management of HF. We've recently shown that acute or chronic hyponatremia, especially <130 mEq/L, was associated with higher loop diuretic dose requirements and more frequent need for escalation of the diuretic regimen to achieve the same level of diuresis as normonatremic HF patients. Aquaresis with tolvaptan represents a potentially advantageous approach to the management of volume overload in HF, especially in patients presenting with concomitant hyponatremia. The purpose of the current study is to prospectively evaluate the comparative efficacy and safety of a tolvaptan-based diuretic regimen compared to conventional diuresis with a furosemide-based regimen on short-term clinical and treatment outcomes in hyponatremic acute HF patients.

This will be a prospective, open-label, parallel-group, randomized study comparing a tolvaptan-based aquaretic regimen to a conventional continuous infusion loop diuretic-based regimen of furosemide. Up to 55 (target sample size of 50) adult subjects admitted with acute HF and signs of volume overload, and serum sodium less than 135 mEq/L will be randomized to tolvaptan or furosemide treatment arms. The initial 24 hours of study treatment will compare tolvaptan monotherapy to furosemide monotherapy. After the initial 24 hours, treatment regimens may be altered to achieve desired clinical goals. Patients will be followed for up to 96 hours and at discharge for study purposes.

Condition or Disease	Intervention/Treatment	Phase
Heart Failure	Drug: Tolvaptan; Drug: Furosemide	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 33 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Aquaresis Utility for Hyponatremic Acute Heart Failure Study
• Study Start Date: Dec 1, 2014
• Actual Primary Completion Date: Feb 1, 2018
• Actual Study Completion Date: Mar 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tolvaptan Tolvaptan 30-60mg once daily (with rescue loop diuretic or metolazone)	Drug: Tolvaptan; Other Names: Samsca
Active Comparator: Furosemide Furosemide continuous infusion 5mg/h with option to titrate (with rescue metolazone)	Drug: Furosemide; Other Names: Lasix

Outcome Measures

Primary Outcome Measures

1. Median Urine Output at 24 Hours Post Randomization [24 hours post randomization]

Secondary Outcome Measures

1. Median Change in Serum Creatinine at 24 Hours Post Randomization [24 hours post randomization]

   Comparison between baseline and 24 hours post randomization concentrations.

Other Outcome Measures

1. Total Urine Output [Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days]

2. Glomerular Filtration Rate (Estimated) [Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days]

3. In-hospital Mortality [Participants will be followed for the duration of hospital stay, an expected average of 5 days]

4. Mean Hourly Urine Output at 24 Hours [Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days]

5. Serum Sodium Change [Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days]

   Difference assessed at baseline, 8, 24, 48, 72 and 96 hours.

6. Weight Change [Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days]

   Difference assessed at baseline, 8, 24, 48, 72 and 96 hours.

7. Cumulative Furosemide Dose [Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days]

8. Cumulative Metolazone Use [Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days]

9. Change in Self-rated Dyspnea [At baseline, 24 and 96 hours post randomization]

10. Acute Worsening of Kidney Function (Defined as an Increase in Serum Creatinine 0.3 mg/dL or 25% Above Baseline) [Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days]

11. Incidence of Electrolyte Abnormalities [Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days]

    Hypo- and hyperkalemia defined as outside the range of 3.5 to 5.0 mEq/L Hypo- and hypermagnesemia defined as outside the range of 1.5-2.4 mEq/L

12. Symptomatic Hypotension [Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days]

13. Change in Plasma Renin Activity [At baseline, 24 and 96 hours post randomization]

14. Change in Copeptin [At baseline, 24 and 96 hours post randomization]

15. Change in N-terminal Pro-B-type Natriuretic Peptide [At baseline, 24 and 96 hours post randomization]

16. Change in Cystatin C [At baseline, 24 and 96 hours post randomization]

17. Change in Urinary Neutrophil Gelatinase-associated Lipocalin (NGAL) [At baseline, 24, 48, 72 and 96 hours post randomization]

18. Hospital Length of Stay [Participants will be followed for the duration of hospital stay, an expected average of 5 days]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Acute HF with signs or symptoms of volume overload [i.e. elevated jugular venous pulsation (JVP), rales, edema]

• Serum sodium < 135 mEq/L at time of or within first 48 hours of hospitalization

• Randomized within 48 hours of presentation to hospital

• ≥ 18 years of age

• Informed consent

Exclusion Criteria:

• Severe symptomatic hyponatremia requiring acute treatment

• Severe renal impairment upon admission (creatinine clearance < 20 mL/min)

• Renal replacement therapy dependent, or requiring upon admission

• Acute coronary syndrome on admission

• Requires or has a mechanical circulatory support device

• Evidence of cardiogenic shock requiring intravenous vasopressors

• Pregnancy

• Patient requiring concomitant use of strong CYP3A4 inhibitors (clarithromycin, ketoconazole, itraconazole, ritonavir, indinavir, nelfinavir, saquinavir, nefazodone, and telithromycin)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Keck Medical Center of USC	Los Angeles	California	United States	90033
2	LAC+USC Medical Center	Los Angeles	California	United States	90033

Sponsors and Collaborators

• University of Southern California
• Otsuka America Pharmaceutical

Investigators

• Principal Investigator: Tien Ng, PharmD, University of Southern California
• Principal Investigator: Uri Elkayam, MD, University of Southern California

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 9, 2017

More Information

Publications

None provided.

• Responsible Party: Tien Ng, Associate Professor of Clinical Pharmacy and Medicine, University of Southern California
• ClinicalTrials.gov Identifier: NCT02183792
• Other Study ID Numbers: HS-13-00705
• First Posted: Jul 8, 2014
• Last Update Posted: May 28, 2019
• Last Verified: May 1, 2019

• Additional relevant MeSH terms: Heart Failure; Furosemide; Tolvaptan

Study Results

Participant Flow

Arm/Group Title	Tolvaptan	Furosemide
Arm/Group Description	Tolvaptan 30-60mg once daily (with rescue loop diuretic or metolazone) Tolvaptan	Furosemide continuous infusion 5mg/h with option to titrate (with rescue metolazone) Furosemide
Period Title: Overall Study
STARTED	18	15
COMPLETED	18	15
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Tolvaptan	Furosemide	Total
Arm/Group Description	Tolvaptan 30-60mg once daily (with rescue loop diuretic or metolazone) Tolvaptan	Furosemide continuous infusion 5mg/h with option to titrate (with rescue metolazone) Furosemide	Total of all reporting groups
Overall Participants	18	15	33
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	53 (11.7)	59 (8.9)	56 (10.8)
Sex: Female, Male (Count of Participants)
Female	7 38.9%	1 6.7%	8 24.2%
Male	11 61.1%	14 93.3%	25 75.8%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (participants) [Number]
United States	18 100%	15 100%	33 100%
Home Loop Diuretic Dose (Furosemide equivalents) (mg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg]	93 (63.5)	108 (77.5)	100 (68.5)

Outcome Measures

1. Primary Outcome

Title	Median Urine Output at 24 Hours Post Randomization
Time Frame	24 hours post randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tolvaptan	Furosemide
Arm/Group Description	Tolvaptan 30-60mg once daily (with rescue loop diuretic or metolazone) Tolvaptan	Furosemide continuous infusion 5mg/h with option to titrate (with rescue metolazone) Furosemide
Measure Participants	18	15
Median (Inter-Quartile Range) [mL]	2910	3150

2. Secondary Outcome

Title	Median Change in Serum Creatinine at 24 Hours Post Randomization
Description	Comparison between baseline and 24 hours post randomization concentrations.
Time Frame	24 hours post randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tolvaptan	Furosemide
Arm/Group Description	Tolvaptan 30-60mg once daily (with rescue loop diuretic or metolazone) Tolvaptan	Furosemide continuous infusion 5mg/h with option to titrate (with rescue metolazone) Furosemide
Measure Participants	18	15
Median Scr at Baseline	1.15	0.87
Median Scr at 24h	1.06	0.96
Median 24h Change	-0.08	-0.01

3. Other Pre-specified Outcome

Title	Total Urine Output
Time Frame	Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Other Pre-specified Outcome

Title	Glomerular Filtration Rate (Estimated)
Time Frame	Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Other Pre-specified Outcome

Title	In-hospital Mortality
Time Frame	Participants will be followed for the duration of hospital stay, an expected average of 5 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Other Pre-specified Outcome

Title	Mean Hourly Urine Output at 24 Hours
Time Frame	Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Other Pre-specified Outcome

Title	Serum Sodium Change
Description	Difference assessed at baseline, 8, 24, 48, 72 and 96 hours.
Time Frame	Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Other Pre-specified Outcome

Title	Weight Change
Description	Difference assessed at baseline, 8, 24, 48, 72 and 96 hours.
Time Frame	Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Other Pre-specified Outcome

Title	Cumulative Furosemide Dose
Time Frame	Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Other Pre-specified Outcome

Title	Cumulative Metolazone Use
Time Frame	Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

11. Other Pre-specified Outcome

Title	Change in Self-rated Dyspnea
Time Frame	At baseline, 24 and 96 hours post randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

12. Other Pre-specified Outcome

Title	Acute Worsening of Kidney Function (Defined as an Increase in Serum Creatinine 0.3 mg/dL or 25% Above Baseline)
Time Frame	Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

13. Other Pre-specified Outcome

Title	Incidence of Electrolyte Abnormalities
Description	Hypo- and hyperkalemia defined as outside the range of 3.5 to 5.0 mEq/L Hypo- and hypermagnesemia defined as outside the range of 1.5-2.4 mEq/L
Time Frame	Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

14. Other Pre-specified Outcome

Title	Symptomatic Hypotension
Time Frame	Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

15. Other Pre-specified Outcome

Title	Change in Plasma Renin Activity
Time Frame	At baseline, 24 and 96 hours post randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

16. Other Pre-specified Outcome

Title	Change in Copeptin
Time Frame	At baseline, 24 and 96 hours post randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

17. Other Pre-specified Outcome

Title	Change in N-terminal Pro-B-type Natriuretic Peptide
Time Frame	At baseline, 24 and 96 hours post randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

18. Other Pre-specified Outcome

Title	Change in Cystatin C
Time Frame	At baseline, 24 and 96 hours post randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

19. Other Pre-specified Outcome

Title	Change in Urinary Neutrophil Gelatinase-associated Lipocalin (NGAL)
Time Frame	At baseline, 24, 48, 72 and 96 hours post randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

20. Other Pre-specified Outcome

Title	Hospital Length of Stay
Time Frame	Participants will be followed for the duration of hospital stay, an expected average of 5 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	During hospitalization (up to 96 hours post randomization)
Arm/Group Title	Tolvaptan		Furosemide
Arm/Group Description	Tolvaptan 30-60mg once daily (with rescue loop diuretic or metolazone) Tolvaptan		Furosemide continuous infusion 5mg/h with option to titrate (with rescue metolazone) Furosemide
All Cause Mortality
	Tolvaptan		Furosemide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/15 (0%)
Serious Adverse Events
	Tolvaptan		Furosemide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	Tolvaptan		Furosemide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/15 (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.