Efficacy and Safety of Ularitide for the Treatment of Acute Decompensated Heart Failure

NCT ID: NCT01661634

Last Updated: 2018-10-23

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 2157 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-07-31
• Study Completion Date: 2016-03-31

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.

Conditions

Acute Decompensated Heart Failure

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Ularitide

Ularitide, lyophilizate for i.v. infusion, 15 ng/kg BW/min, for 48 hours

Group Type: EXPERIMENTAL

Ularitide

Intervention Type: DRUG

Placebo

Placebo lyophilizate for i.v. infusion

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Interventions

Ularitide

Intervention Type: DRUG

Placebo

Intervention Type: DRUG

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Quintiles, Inc.

INDUSTRY

Sponsor Role: collaborator

Cardiorentis

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Milton Packer, MD

Role: STUDY_CHAIR

Christopher O'Connor, MD

Role: PRINCIPAL_INVESTIGATOR

William F. Peacock, MD

Role: PRINCIPAL_INVESTIGATOR

Locations

Huntsville, Alabama, United States

Montgomery, Alabama, United States

Sacramento, California, United States

Littleton, Colorado, United States

Trumbull, Connecticut, United States

Washington D.C., District of Columbia, United States

Jacksonville, Florida, United States

Lawrenceville, Georgia, United States

Peoria, Illinois, United States

Rockford, Illinois, United States

Kansas City, Kansas, United States

Alexandria, Louisiana, United States

Worcester, Massachusetts, United States

Detroit, Michigan, United States

Detroit, Michigan, United States

Detroit, Michigan, United States

Royal Oak, Michigan, United States

Minneapolis, Minnesota, United States

St Louis, Missouri, United States

Lincoln, Nebraska, United States

Newark, New Jersey, United States

Brooklyn, New York, United States

The Bronx, New York, United States

Cincinnati, Ohio, United States

Columbus, Ohio, United States

Middletown, Ohio, United States

Toledo, Ohio, United States

Philadelphia, Pennsylvania, United States

Charleston, South Carolina, United States

Chattanooga, Tennessee, United States

Nashville, Tennessee, United States

Austin, Texas, United States

Dallas, Texas, United States

Fort Worth, Texas, United States

Houston, Texas, United States

Charlottesville, Virginia, United States

Midlothian, Virginia, United States

Norfolk, Virginia, United States

Salem, Virginia, United States

Ciudad Autonoma, Buenos Aires, Argentina

Coronel Suárez, Buenos Aires, Argentina

La Plata, Buenos Aires, Argentina

Córdoba, Córdoba Province, Argentina

San Vicente, Córdoba Province, Argentina

Rosario, Santa Fe Province, Argentina

San Miguel de Tucumán, Tucumán Province, Argentina

Corrientes, , Argentina

Córdoba, , Argentina

Córdoba, , Argentina

Córdoba, , Argentina

Córdoba, , Argentina

Córdoba, , Argentina

San Miguel de Tucumán, , Argentina

Santa Fe, , Argentina

Santa Fe, , Argentina

Aalst, , Belgium

Kortrijk, , Belgium

Goiânia, Goiás, Brazil

Porto Alegre, Rio Grande do Sul, Brazil

Campinas, São Paulo, Brazil

São José do Rio Preto, São Paulo, Brazil

São Paulo, São Paulo, Brazil

Halifax, Nova Scotia, Canada

Montreal, Quebec, Canada

Montreal, Quebec, Canada

Brno, , Czechia

Brno, , Czechia

Frýdek-Místek, , Czechia

Hradec Králové, , Czechia

Olomouc, , Czechia

Prague, , Czechia

Prague, , Czechia

Prague, , Czechia

Prague, , Czechia

Prague, , Czechia

Znojmo, , Czechia

Tallinn, , Estonia

Tallinn, , Estonia

Espoo, , Finland

Besançon, Doubs, France

Toulouse, Haute Garonne, France

Paris, Paris, France

Bayonne, Pyrenees Atlantiques, France

Bron, Rhone, France

Poitiers, Vienne, France

Nuremberg, Bavaria, Germany

Bad Nauheim, Hesse, Germany

Groß-Umstadt, Hesse, Germany

Langen, Hesse, Germany

Greifswald, Mecklenburg-Vorpommern, Germany

Bochum, North Rhine-Westphalia, Germany

Erfurt, Thuringia, Germany

Jena, Thuringia, Germany

Berlin, , Germany

Berlin, , Germany

Berlin, , Germany

Debrecen, , Hungary

Afula, , Israel

Ashkelon, , Israel

Hadera, , Israel

Holon, , Israel

Kfar Saba, , Israel

Nahariya, , Israel

Nazareth, , Israel

Safed, , Israel

San Fermo della Battaglia, Como, Italy

Legnano, Milano, Italy

Rozzano, Milano, Italy

Alessandria, , Italy

Bari, , Italy

Bologna, , Italy

Como, , Italy

Genova, , Italy

Milan, , Italy

Milan, , Italy

Napoli, , Italy

Novara, , Italy

Roma, , Italy

Varese, , Italy

Riga, , Latvia

Kaunas, , Lithuania

Kaunas, , Lithuania

Vilnius, , Lithuania

Beverwijk, , Netherlands

Ede, , Netherlands

Gorinchem, , Netherlands

Groningen, , Netherlands

Leiderdorp, , Netherlands

Sneek, , Netherlands

Krakow, , Poland

Krakow, , Poland

Lodz, , Poland

Warsaw, , Poland

Warsaw, , Poland

Wroclaw, , Poland

Bucharest, , Romania

Bucharest, , Romania

Iași, , Romania

Oradea, , Romania

Belgrade, , Serbia

Belgrade, , Serbia

Belgrade, , Serbia

Kamenitz, , Serbia

Niš, , Serbia

Niška Banja, , Serbia

Zemun, , Serbia

L'Hospitalet de Llobregat, Barcelona, Spain

Sant Joan Despí, Barcelona, Spain

Santiago de Compostela, La Coruña, Spain

Aranjuez, Madrid, Spain

Majadahonda, Madrid, Spain

Majadahonda, Madrid, Spain

Alicante, , Spain

Barcelona, , Spain

Barcelona, , Spain

Madrid, , Spain

Basel, , Switzerland

Lugano, , Switzerland

Zurich, , Switzerland

Eskişehir, , Turkey (Türkiye)

Istanbul, , Turkey (Türkiye)

Kocaeli, , Turkey (Türkiye)

Sivas, , Turkey (Türkiye)

Countries

United States; Argentina; Belgium; Brazil; Canada; Czechia; Estonia; Finland; France; Germany; Hungary; Israel; Italy; Latvia; Lithuania; Netherlands; Poland; Romania; Serbia; Spain; Switzerland; Turkey (Türkiye)

References

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.

Reference Type: BACKGROUND

PMID: 16338265 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 17074775 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 28402745 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 27862700 (View on PubMed)

Other Identifiers

2010-024249-59

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

ULA01

Identifier Type: -

Identifier Source: org_study_id