Clinical trial NCT01661634: Efficacy and Safety of Ularitide for the Treatment of Acute Decompensated Heart Failure
Official title: Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of Ularitide (Urodilatin) Intravenous Infusion in Patients Suffering From Acute Decompensated Heart Failure [TRUE-AHF]
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Acute Decompensated Heart Failure
Keywords: Acute decompensated heart failure
Lead sponsor: Cardiorentis
Sponsor class: INDUSTRY
Collaborators: name: Quintiles, Inc.
First posted: 2012-08-09
Enrollment: 2157
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the efficacy and safety of a continuous intravenous (IV) ularitide infusion on the clinical status and outcome of patients with acute decompensated heart failure (ADHF).

Detailed description: The objective of the TRUE-AHF study is to evaluate the effect of a 48-h continuous IV infusion of ularitide (15 ng/kg/min) versus placebo on the clinical status of patients with acute decompensated heart failure (ADHF).

The study drug will be administered in addition to the standard treatment. The nature of standard therapy will be carried out according to the clinical judgment of the Investigator and may include vasodilator, inotropic, and diuretic drugs, as clinically indicated.

There are two co-primary endpoints for this study. Co-primary endpoint 1 will be a hierarchical clinical composite variable that includes a patient-centered assessment of clinical progress, an assessment of lack of improvement or worsening of HF requiring a pre-specified intervention, and death.

The endpoint is intended to mimic the assessment that would be carried out by a physician caring for the patient. If, during the 48 h infusion, a patient's clinical course deteriorates because he/she dies, fails to improve or develops worsening HF requiring a pre-specified intervention or if the patient considers his/her general clinical status as moderately or markedly worse, the patient will be considered to be "worse". If the patient considers his/her general clinical status as moderately or markedly improved and if such improvement is sustained without fulfilling the criteria for "worse" throughout the 48-h infusion (from 0 h to 48 h), the patient will be considered to be "improved". If the patient is neither improved nor worse, the patient's clinical status will be considered to be "unchanged".

Co-primary efficacy endpoint 2 evaluates freedom from cardiovascular mortality during follow up after randomization, for the entire duration of the trial.

Eligibility criteria: Inclusion Criteria:

1. Males and females aged 18 to 85 years.
2. Unplanned hospitalization or emergency department visit for ADHF. Acute HF is defined as including all of the following:

   * Dyspnea at rest in a recumbent sitting position (30 to 45 degrees), which has worsened within the past week;
   * Radiological evidence of HF on a chest X-ray (if an appropriate chest;
   * computerized tomography scan is done; the X-ray need not be performed);
   * Brain natriuretic peptide (BNP) \>500 pg/mL or NT-pro BNP \>2000 pg/mL.
3. Ability to start infusion of the study drug within 12 h after initial clinical assessment.
4. Ability to reliably carry out self-assessment of symptoms.
5. Systolic blood pressure ≥116 mmHg and ≤180 mmHg at the time of randomization.
6. Persisting dyspnea at rest despite standard background therapy for ADHF (as determined by the Investigator) which must include IV furosemide (or equivalent diuretic) at ≥40 mg (or its equivalent) at any time after start of emergency services (ambulance, emergency department, or hospital). At the time of randomization, the patient must still be symptomatic. In addition, the patient should not have received an IV bolus of a diuretic for at least 2 h prior to randomization, and the infusion rates of all ongoing IV infusions of medications to treat HF must not have been increased or decreased for at least 2 h prior to randomization.
7. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local privacy regulations).

Exclusion Criteria:

1. Known active myocarditis, obstructive hypertrophic cardiomyopathy, congenital heart disease, restrictive cardiomyopathy, constrictive pericarditis, uncorrected clinically significant primary valvular disease.
2. Treatment with dobutamine at a dose \>5 μg/kg/min or use of drugs for support of BP at the time of randomization.
3. Treatment with levosimendan, milrinone, or any other phosphodiesterase inhibitor within 7 days before randomization.
4. Treatment with nesiritide within 30 days before randomization.
5. Creatinine clearance \<25 mL/min/1.73m² (as measured by the MDRD formula) at the time of screening.
6. Planned coronary revascularization procedure (percutaneous coronary intervention or coronary artery bypass grafting) within 5 days of randomization.
7. Clinical diagnosis of acute coronary syndrome meeting any 2 of the following 3 criteria:

   1. Prolonged chest pain at rest, or an accelerated pattern of angina
   2. Electrocardiogram changes indicative of ischemia or myocardial injury defined as: a new ST elevation at the J point of two anatomically contiguous leads with the cut-off points: ≥0.2 mV in men ≥40 years (\>0.25 mV in men \<40 years) or ≥0.15 mV in women in leads V2-V3 and/or ≥0.1 mV in other leads; or ST depression and T wave changes. New horizontal or down sloping ST depression ≥0.05 mV in two contiguous leads; and/or new T inversion ≥0.3 mV in two contiguous leads.
   3. Serum troponin \>3 times upper limit of normal.
8. Clinically suspected acute mechanical cause of ADHF (e.g., papillary muscular rupture). The diagnosis need not be confirmed by imaging or cardiac catheterization.
9. Anemia (hemoglobin \<9 g/dL or a hematocrit \<25%).
10. Known vasculitis, active infective endocarditis, or suspected infections, e.g., pneumonia, acute hepatitis, systemic inflammatory response syndrome, or sepsis.
11. Body temperature ≥38°C just prior to randomization.
12. Acute or chronic respiratory disorder (e.g., severe chronic obstructive pulmonary disease) or primary pulmonary hypertension sufficient to cause dyspnea at rest, which may interfere with the ability to interpret dyspnea assessments or hemodynamic measurements.
13. Terminal illness other than congestive HF with expected survival \<180 days.
14. Any previous exposure to ularitide.
15. Known allergy to natriuretic peptides.
16. Participation in an investigational clinical drug study within 30 days prior to randomization.
17. Current drug abuse or chronic alcoholism sufficient to impair participation and compliance to the study protocol.
18. Women who are breast-feeding.
19. Women of child-bearing potential (i.e., pre-menopausal women) without documentation of a negative urine/blood pregnancy assay within 12 h prior to randomization.
20. Any condition that, in the Investigator's opinion, makes the patient unsuitable for study participation.
21. Legal incapacity or limited legal capacity.
22. Patients requiring mechanical circulatory support.
23. Patients with severe hepatic impairment.

Primary outcomes:
measure: Two Co-primary Efficacy Endpoints
timeFrame: 6, 24, 48 hours post infusion through the entire duration of the trial
Secondary outcomes:
measure: Length of stay of index hospitalization in hours after start of study drug infusion
timeFrame: up to 30 days
measure: Length of stay in intensive care (intensive care unit [ICU] or critical care unit [CCU])
timeFrame: during the first 120 h following the start of the study drug infusion.
measure: Number of events of persistent or worsening HF requiring an intervention
timeFrame: from the start of the study drug infusion to 120 h.
measure: Proportion of patients with persistent or worsening HF and requiring an intervention
timeFrame: from the start of study drug infusion to 120 h.
measure: Reduction in rehospitalization for heart failure
timeFrame: within 30 days after initial hospital
measure: Changes of N-terminal pro brain natriuretic peptide (NT-pro BNP)
timeFrame: 48 h of treatment compared to baseline.
measure: Time to completion of last dose of any IV drugs that can be used for the treatment of HF (e.g., diuretics, vasodilators, or positive inotropic agents)
timeFrame: for the first 120 h following the start of the drug infusion.
measure: Change in serum creatinine
timeFrame: from baseline through 72 h.
measure: 180 days after start of study drug infusion, including patients still hospitalized at Day 30.
timeFrame: All-cause mortality and cardiovascular rehospitalization
Other outcomes:
Locations:
city: Huntsville
country: United States
state: Alabama
city: Montgomery
country: United States
state: Alabama
city: Sacramento
country: United States
state: California
city: Littleton
country: United States
state: Colorado
city: Trumbull
country: United States
state: Connecticut
city: Washington
country: United States
state: District of Columbia
city: Jacksonville
country: United States
state: Florida
city: Lawrenceville
country: United States
state: Georgia
city: Peoria
country: United States
state: Illinois
city: Rockford
country: United States
state: Illinois
city: Kansas City
country: United States
state: Kansas
city: Alexandria
country: United States
state: Louisiana
city: Worcester
country: United States
state: Massachusetts
city: Detroit
country: United States
state: Michigan
city: Detroit
country: United States
state: Michigan
city: Detroit
country: United States
state: Michigan
city: Royal Oak
country: United States
state: Michigan
city: Minneapolis
country: United States
state: Minnesota
city: Saint Louis
country: United States
state: Missouri
city: Lincoln
country: United States
state: Nebraska
city: Newark
country: United States
state: New Jersey
city: Bronx
country: United States
state: New York
city: Brooklyn
country: United States
state: New York
city: Cincinnati
country: United States
state: Ohio
city: Columbus
country: United States
state: Ohio
city: Middletown
country: United States
state: Ohio
city: Toledo
country: United States
state: Ohio
city: Philadelphia
country: United States
state: Pennsylvania
city: Charleston
country: United States
state: South Carolina
city: Chattanooga
country: United States
state: Tennessee
city: Nashville
country: United States
state: Tennessee
city: Austin
country: United States
state: Texas
city: Dallas
country: United States
state: Texas
city: Fort Worth
country: United States
state: Texas
city: Houston
country: United States
state: Texas
city: Charlottesville
country: United States
state: Virginia
city: Midlothian
country: United States
state: Virginia
city: Norfolk
country: United States
state: Virginia
city: Salem
country: United States
state: Virginia
city: Ciudad Autonoma
country: Argentina
state: Buenos Aires
city: Coronel Suarez
country: Argentina
state: Buenos Aires
city: La Plata
country: Argentina
state: Buenos Aires
city: Córdoba
country: Argentina
state: Cordoba
city: San Vicente
country: Argentina
state: Cordoba
city: Rosario
country: Argentina
state: Santa Fe
city: San Miguel de Tucuman
country: Argentina
state: Tucuman
city: Cordoba
country: Argentina
city: Cordoba
country: Argentina
city: Cordoba
country: Argentina
city: Cordoba
country: Argentina
city: Cordoba
country: Argentina
city: Corrientes
country: Argentina
city: San Miguel de Tucuman
country: Argentina
city: Santa Fe
country: Argentina
city: Santa Fe
country: Argentina
city: Aalst
country: Belgium
city: Kortrijk
country: Belgium
city: Goiânia
country: Brazil
state: Goiás
city: Porto Alegre
country: Brazil
state: Rio Grande Do Sul
city: Campinas
country: Brazil
state: Sao Paulo
city: São José do Rio Preto
country: Brazil
state: Sao Paulo
city: São Paulo
country: Brazil
state: Sao Paulo
city: Halifax
country: Canada
state: Nova Scotia
city: Montreal
country: Canada
state: Quebec
city: Montréal
country: Canada
state: Quebec
city: Brno
country: Czechia
city: Brno
country: Czechia
city: Frydek-Mistek
country: Czechia
city: Hradec Kralove
country: Czechia
city: Olomouc
country: Czechia
city: Praha 10
country: Czechia
city: Praha 2
country: Czechia
city: Praha 4
country: Czechia
city: Praha 5
country: Czechia
city: Praha 5
country: Czechia
city: Znojmo
country: Czechia
city: Tallinn
country: Estonia
city: Tallinn
country: Estonia
city: Espoo
country: Finland
city: Besançon Cedex
country: France
state: Doubs
city: Toulouse Cedex 9
country: France
state: Haute Garonne
city: Paris cedex 10
country: France
state: Paris
city: Bayonne
country: France
state: Pyrenees Atlantiques
city: Bron cedex
country: France
state: Rhone
city: Poitiers
country: France
state: Vienne
city: Nuernberg
country: Germany
state: Bayern
city: Bad Nauheim
country: Germany
state: Hessen
city: Gross-Umstadt
country: Germany
state: Hessen
city: Langen
country: Germany
state: Hessen
city: Greifswald
country: Germany
state: Mecklenburg Vorpommern
city: Bochum
country: Germany
state: Nordrhein Westfalen
city: Erfurt
country: Germany
state: Thueringen
city: Jena
country: Germany
state: Thueringen
city: Berlin
country: Germany
city: Berlin
country: Germany
city: Berlin
country: Germany
city: Debrecen
country: Hungary
city: Afula
country: Israel
city: Ashkelon
country: Israel
city: Hadera
country: Israel
city: Holon
country: Israel
city: Kfar-Saba
country: Israel
city: Nahariya
country: Israel
city: Nazareth
country: Israel
city: Safed
country: Israel
city: San Fermo della Battaglia
country: Italy
state: Como
city: Legnano
country: Italy
state: Milano
city: Rozzano
country: Italy
state: Milano
city: Alessandria
country: Italy
city: Bari
country: Italy
city: Bologna
country: Italy
city: Como
country: Italy
city: Genova
country: Italy
city: Milano
country: Italy
city: Milano
country: Italy
city: Napoli
country: Italy
city: Novara
country: Italy
city: Roma
country: Italy
city: Varese
country: Italy
city: Riga
country: Latvia
city: Kaunas
country: Lithuania
city: Kaunas
country: Lithuania
city: Vilnius
country: Lithuania
city: Beverwijk
country: Netherlands
city: Ede
country: Netherlands
city: Gorinchem
country: Netherlands
city: Groningen
country: Netherlands
city: Leiderdorp
country: Netherlands
city: Sneek
country: Netherlands
city: Krakow
country: Poland
city: Krakow
country: Poland
city: Lodz
country: Poland
city: Warszawa
country: Poland
city: Warszawa
country: Poland
city: Wroclaw
country: Poland
city: Bucuresti
country: Romania
city: Bucuresti
country: Romania
city: Iasi
country: Romania
city: Oradea
country: Romania
city: Belgrade
country: Serbia
city: Belgrade
country: Serbia
city: Belgrade
country: Serbia
city: Niska Banja
country: Serbia
city: Nis
country: Serbia
city: Sremska Kamenica
country: Serbia
city: Zemun
country: Serbia
city: L'Hospitalet de Llobregat
country: Spain
state: Barcelona
city: Sant Joan Despí
country: Spain
state: Barcelona
city: Santiago de Compostela
country: Spain
state: La Coruña
city: Aranjuez
country: Spain
state: Madrid
city: Majadahonda
country: Spain
state: Madrid
city: Majadahonda
country: Spain
state: Madrid
city: Alicante
country: Spain
city: Barcelona
country: Spain
city: Barcelona
country: Spain
city: Madrid
country: Spain
city: Basel
country: Switzerland
city: Lugano
country: Switzerland
city: Zuerich
country: Switzerland
city: Eskisehir
country: Turkey
city: Istanbul
country: Turkey
city: Kocaeli
country: Turkey
city: Sivas
country: Turkey
Study officials:
name: Milton Packer, MD
role: STUDY_CHAIR
name: Christopher O'Connor, MD
role: PRINCIPAL_INVESTIGATOR
name: William F. Peacock, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Mitrovic V, Luss H, Nitsche K, Forssmann K, Maronde E, Fricke K, Forssmann WG, Meyer M. Effects of the renal natriuretic peptide urodilatin (ularitide) in patients with decompensated chronic heart failure: a double-blind, placebo-controlled, ascending-dose trial. Am Heart J. 2005 Dec;150(6):1239. doi: 10.1016/j.ahj.2005.01.022.
citation: Mitrovic V, Seferovic PM, Simeunovic D, Ristic AD, Miric M, Moiseyev VS, Kobalava Z, Nitsche K, Forssmann WG, Luss H, Meyer M. Haemodynamic and clinical effects of ularitide in decompensated heart failure. Eur Heart J. 2006 Dec;27(23):2823-32. doi: 10.1093/eurheartj/ehl337. Epub 2006 Oct 30.
citation: Packer M, O'Connor C, McMurray JJV, Wittes J, Abraham WT, Anker SD, Dickstein K, Filippatos G, Holcomb R, Krum H, Maggioni AP, Mebazaa A, Peacock WF, Petrie MC, Ponikowski P, Ruschitzka F, van Veldhuisen DJ, Kowarski LS, Schactman M, Holzmeister J; TRUE-AHF Investigators. Effect of Ularitide on Cardiovascular Mortality in Acute Heart Failure. N Engl J Med. 2017 May 18;376(20):1956-1964. doi: 10.1056/NEJMoa1601895. Epub 2017 Apr 12.
citation: Packer M, Holcomb R, Abraham WT, Anker S, Dickstein K, Filippatos G, Krum H, Maggioni AP, McMurray JJV, Mebazaa A, O'Connor C, Peacock F, Ponikowski P, Ruschitzka F, van Veldhuisen DJ, Holzmeister J; TRUE-AHF Investigators and Committees. Rationale for and design of the TRUE-AHF trial: the effects of ularitide on the short-term clinical course and long-term mortality of patients with acute heart failure. Eur J Heart Fail. 2017 May;19(5):673-681. doi: 10.1002/ejhf.698. Epub 2016 Nov 13.