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

NCT01661634 | Completed Phase 3 DMC

• 2 other identifiers: ULA012010-024249-59
• Study Type: interventional
• Target: 2,157
• Locations: 21 countries
• Sites: 161

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).

Conditions

Acute Decompensated Heart Failure

Keywords

Acute decompensated heart failure

Outcome Measures

Primary Outcomes (1)

• Two Co-primary Efficacy Endpoints

  Improvement in a hierarchical clinical composite comprised of elements associated with: patient global assessment using a 7-point scale of symptomatic improvement, lack of improvement, or worsening; persistent or worsening heart failure (HF) requiring an intervention (initiation or intensification of IV therapy, circulatory or ventilatory mechanical support, surgical intervention, ultrafiltration, hemofiltration or dialysis); and all-cause mortality. Assessment of the clinical composite will be performed at 6 hour (h), 24 h and 48 h after start of IV ularitide infusion Freedom from cardiovascular mortality during follow up after randomization, for the entire duration of the trial.

  6, 24, 48 hours post infusion through the entire duration of the trial

Secondary Outcomes (9)

• Length of stay of index hospitalization in hours after start of study drug infusion

  up to 30 days

• Length of stay in intensive care (intensive care unit [ICU] or critical care unit [CCU])

  during the first 120 h following the start of the study drug infusion.

• Number of events of persistent or worsening HF requiring an intervention

  from the start of the study drug infusion to 120 h.

• Proportion of patients with persistent or worsening HF and requiring an intervention

  from the start of study drug infusion to 120 h.

• Reduction in rehospitalization for heart failure

  within 30 days after initial hospital

Study Arms (2)

Ularitide

EXPERIMENTAL

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

Drug: Ularitide

Placebo

PLACEBO COMPARATOR

Placebo lyophilizate for i.v. infusion

Drug: Placebo

Interventions

Ularitide DRUG

Ularitide

Placebo DRUG

Placebo

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Males and females aged 18 to 85 years.
• 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.
• Ability to start infusion of the study drug within 12 h after initial clinical assessment.
• Ability to reliably carry out self-assessment of symptoms.
• Systolic blood pressure ≥116 mmHg and ≤180 mmHg at the time of randomization.
• 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.
• 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).

You may not qualify if:

• Known active myocarditis, obstructive hypertrophic cardiomyopathy, congenital heart disease, restrictive cardiomyopathy, constrictive pericarditis, uncorrected clinically significant primary valvular disease.
• Treatment with dobutamine at a dose \>5 μg/kg/min or use of drugs for support of BP at the time of randomization.
• Treatment with levosimendan, milrinone, or any other phosphodiesterase inhibitor within 7 days before randomization.
• Treatment with nesiritide within 30 days before randomization.
• Creatinine clearance \<25 mL/min/1.73m² (as measured by the MDRD formula) at the time of screening.
• Planned coronary revascularization procedure (percutaneous coronary intervention or coronary artery bypass grafting) within 5 days of randomization.
• Clinical diagnosis of acute coronary syndrome meeting any 2 of the following 3 criteria:
• Prolonged chest pain at rest, or an accelerated pattern of angina
• 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.
• Serum troponin \>3 times upper limit of normal.
• Clinically suspected acute mechanical cause of ADHF (e.g., papillary muscular rupture). The diagnosis need not be confirmed by imaging or cardiac catheterization.
• Anemia (hemoglobin \<9 g/dL or a hematocrit \<25%).
• Known vasculitis, active infective endocarditis, or suspected infections, e.g., pneumonia, acute hepatitis, systemic inflammatory response syndrome, or sepsis.
• Body temperature ≥38°C just prior to randomization.
• 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.

Sponsors & Collaborators

• Cardiorentis: lead
• Quintiles, Inc.: collaborator

Study Sites (163)

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Huntsville, Alabama, 35801, United States

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Montgomery, Alabama, 36106, United States

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Sacramento, California, 95817, United States

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Littleton, Colorado, 80120, United States

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Trumbull, Connecticut, 06611, United States

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Washington D.C., District of Columbia, 20422, United States

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Jacksonville, Florida, 32216, United States

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Lawrenceville, Georgia, 30046, United States

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Peoria, Illinois, 61606, United States

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Rockford, Illinois, 61107, United States

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Kansas City, Kansas, 66160, United States

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Alexandria, Louisiana, 71303, United States

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Worcester, Massachusetts, 01655, United States

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Detroit, Michigan, 48201, United States

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Detroit, Michigan, 48202, United States

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Detroit, Michigan, 48235, United States

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Royal Oak, Michigan, 48073, United States

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Minneapolis, Minnesota, 55415, United States

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St Louis, Missouri, 63110, United States

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Lincoln, Nebraska, 68526, United States

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Newark, New Jersey, 07107, United States

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Brooklyn, New York, 11203, United States

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The Bronx, New York, 10467, United States

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Cincinnati, Ohio, 45219, United States

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Columbus, Ohio, 43210, United States

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Middletown, Ohio, 45005, United States

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Toledo, Ohio, 43614, United States

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Philadelphia, Pennsylvania, 19141, United States

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Charleston, South Carolina, 29425, United States

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Chattanooga, Tennessee, 37403, United States

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Nashville, Tennessee, 37232, United States

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Austin, Texas, 78758, United States

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Dallas, Texas, 75390, United States

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Fort Worth, Texas, 76104, United States

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Houston, Texas, 77030, United States

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Charlottesville, Virginia, 22908, United States

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Midlothian, Virginia, 23114, United States

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Norfolk, Virginia, 23507, United States

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Salem, Virginia, 24153, United States

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Ciudad Autonoma, Buenos Aires, 1180, Argentina

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Coronel Suárez, Buenos Aires, B7540GHD, Argentina

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La Plata, Buenos Aires, 1900, Argentina

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Córdoba, Córdoba Province, X5008KKF, Argentina

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San Vicente, Córdoba Province, 5006, Argentina

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Rosario, Santa Fe Province, 2000, Argentina

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San Miguel de Tucumán, Tucumán Province, 4000, Argentina

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Corrientes, W3400AMZ, Argentina

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Córdoba, 5000, Argentina

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Córdoba, 5016, Argentina

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Córdoba, X5000JHQ, Argentina

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Córdoba, X5002AOQ, Argentina

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Córdoba, X5004BAL, Argentina

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San Miguel de Tucumán, T4000NIL, Argentina

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Santa Fe, S3000EOZ, Argentina

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Santa Fe, S3000FUJ, Argentina

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Aalst, 9300, Belgium

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Kortrijk, 8500, Belgium

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Goiânia, Goiás, 74605-020, Brazil

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Porto Alegre, Rio Grande do Sul, 90035-003, Brazil

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Campinas, São Paulo, 13060-904, Brazil

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São José do Rio Preto, São Paulo, 15090-000, Brazil

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São Paulo, São Paulo, 05403-000, Brazil

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Halifax, Nova Scotia, B3H 2Y9, Canada

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Montreal, Quebec, H1T1C8, Canada

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Montreal, Quebec, H2W 1T8, Canada

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Brno, 625 00, Czechia

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Brno, 65691, Czechia

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Frýdek-Místek, 73818, Czechia

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Hradec Králové, 50012, Czechia

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Olomouc, 775 20, Czechia

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Prague, 100 34, Czechia

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Prague, 128 08, Czechia

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Prague, 140 00, Czechia

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Prague, 150 06, Czechia

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Prague, 150 30, Czechia

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Znojmo, 669 02, Czechia

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Tallinn, 10138, Estonia

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Tallinn, 13419, Estonia

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Espoo, 02740, Finland

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Besançon, Doubs, 25030, France

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Toulouse, Haute Garonne, 31059, France

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Paris, Paris, 75475, France

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Bayonne, Pyrenees Atlantiques, 64100, France

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Bron, Rhone, 69677, France

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Poitiers, Vienne, 86000, France

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Nuremberg, Bavaria, 90419, Germany

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Bad Nauheim, Hesse, 61231, Germany

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Groß-Umstadt, Hesse, 64823, Germany

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Langen, Hesse, 63225, Germany

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Greifswald, Mecklenburg-Vorpommern, 17475, Germany

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Bochum, North Rhine-Westphalia, 44787, Germany

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Erfurt, Thuringia, 99089, Germany

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Jena, Thuringia, 07743, Germany

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Berlin, 10249, Germany

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Berlin, 12351, Germany

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Berlin, 13353, Germany

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Debrecen, 4032, Hungary

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Afula, 1834111, Israel

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Ashkelon, 7830604, Israel

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Hadera, 38100, Israel

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Holon, 5810001, Israel

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Kfar Saba, 4428164, Israel

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Nahariya, 2210001, Israel

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Nazareth, 1610001, Israel

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Safed, 13100, Israel

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San Fermo della Battaglia, Como, 22020, Italy

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Legnano, Milano, 20025, Italy

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Rozzano, Milano, 20089, Italy

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Alessandria, 15100, Italy

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Bari, 70124, Italy

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Bologna, 40138, Italy

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Como, 22020, Italy

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Genova, 16132, Italy

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Milan, 20138, Italy

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Milan, 20162, Italy

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Napoli, 80131, Italy

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Novara, 28100, Italy

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Roma, 00189, Italy

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Varese, 21100, Italy

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Riga, LV1002, Latvia

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Kaunas, 45130, Lithuania

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Kaunas, 50009, Lithuania

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Vilnius, 08661, Lithuania

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Beverwijk, 1942 LE, Netherlands

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Ede, 6716 RP, Netherlands

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Gorinchem, 4204 AA, Netherlands

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Groningen, 9713 GZ, Netherlands

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Leiderdorp, 2353 GA, Netherlands

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Sneek, 8601 ZK, Netherlands

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Krakow, 31-121, Poland

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Krakow, 31-202, Poland

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Lodz, 91-347, Poland

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Warsaw, 03-242, Poland

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Warsaw, 04-628, Poland

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Wroclaw, 50-981, Poland

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Bucharest, 021659, Romania

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Bucharest, 050098, Romania

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Iași, 700503, Romania

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Oradea, 410169, Romania

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Belgrade, 11000, Serbia

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Belgrade, 11040, Serbia

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Belgrade, 11080, Serbia

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Kamenitz, 21204, Serbia

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Niš, 18000, Serbia

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Niška Banja, 18205, Serbia

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Zemun, 11080, Serbia

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L'Hospitalet de Llobregat, Barcelona, 08907, Spain

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Sant Joan Despí, Barcelona, 08970, Spain

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Santiago de Compostela, La Coruña, 15706, Spain

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Aranjuez, Madrid, 28300, Spain

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Majadahonda, Madrid, 28222, Spain

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Majadahonda, Madrid, 28822, Spain

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Alicante, 03010, Spain

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Barcelona, 08025, Spain

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Barcelona, 08036, Spain

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Madrid, 28040, Spain

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Basel, 4031, Switzerland

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Lugano, 6900, Switzerland

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Zurich, 8091, Switzerland

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Eskişehir, 26480, Turkey (Türkiye)

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Istanbul, 34662, Turkey (Türkiye)

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Kocaeli, 41300, Turkey (Türkiye)

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Sivas, 58140, Turkey (Türkiye)

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Related Publications (4)

• 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.

  PMID: 16338265 BACKGROUND

• 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.

  PMID: 17074775 BACKGROUND

• 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.

  PMID: 28402745 DERIVED

• 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.

  PMID: 27862700 DERIVED

MeSH Terms

Interventions

Ularitide

Study Officials

• Milton Packer, MD

  STUDY CHAIR

• Christopher O'Connor, MD

  PRINCIPAL INVESTIGATOR

• William F. Peacock, MD

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 31, 2012
• First Posted: August 9, 2012
• Study Start: July 1, 2012
• Primary Completion: November 1, 2015
• Study Completion: March 1, 2016
• Last Updated: October 23, 2018

Record last verified: 2018-10

Locations

US (39); IL (8); HU (1); BR (5); FR (6); AR (16); RO (4); CZ (11); LI (3); SE (7); TU (4); ES (10); PL (6); BE (2); DE (11); LA (1); IT (14); NL (6); FI (1); CH (3); CA (3)