Clinical trial NCT00525707: Tezosentan in Acute Heart Failure
Official title: Multicenter, Double-blind, Randomized, Placebo-controlled, Parallel Group Study to Assess the Efficacy, Safety, and Tolerability of Tezosentan in Patients With Acute Heart Failure.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Acute Heart Failure
Acute Decompensation of Chronic Heart Failure
New Onset of Heart Failure
Keywords: acute heart failure
Actelion
tezosentan
acute decompensation of chronic heart failure
New onset of heart failure
Lead sponsor: Idorsia Pharmaceuticals Ltd.
Sponsor class: INDUSTRY
First posted: 2007-09-06
Enrollment: 735
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The randomized patients with acute heart failure will be stratified based on the presence or absence of a Swan-Ganz catheter and assigned to receive either tezosentan 5 mg/h for the first 30 minutes and 1 mg/h thereafter or matching placebo in a 1:1 manner. The duration of the treatment is 24 hours up to 72 hours. The duration of the follow-up period is 30 days after treatment initiation for death, re-hospitalizations and SAEs followed by a follow-up period of 5 months for vital status.


Eligibility criteria: Inclusion Criteria:

1. Patients 18 years of age or older.
2. Male or non-breast-feeding, non-pregnant female (only females who are post menopausal, surgically sterile or practicing a reliable method of contraception).
3. Acute heart failure (ischemic or non-ischemic).
4. Randomization within 24 hours of hospitalization (including emergency room stay) for acute heart failure.
5. Dyspnea at rest as assessed by the patient and breathing rate ³ 24/min (measured during 60 seconds).
6. At least two out of the following four criteria: · elevated BNP or N terminal pro-BNP (more than three times the upper limit of normal for the site) in patients not treated with nesiritide,· clinical evidence of pulmonary congestion/edema (e.g., rales or crackles more than a third above bases),· evidence of pulmonary congestion on chest X-ray, · left ventricular systolic dysfunction (EF \< 40% or wall motion index £ 1.2 within 12 months prior to randomization).
7. Patients in need of i.v. therapy for acute heart failure and who have received at least one dose of i.v. diuretic within 24 hours prior to study drug initiation (last bolus dose must have been more than 2 hours prior to study drug initiation).
8. Written informed consent.

Exclusion Criteria:

Criteria only for patients hemodynamically monitored:

1. Baseline cardiac index \> 2.5 l/min/m2 and/or PCWP \< 20 mmHg within 6 hours prior to study drug initiation.

   Criteria for all patients:
2. Patients not receiving i.v. vasodilators (e.g., nitrates, nitroprusside, nesiritide) at baseline: supine systolic blood pressure \< 100 mmHg. Patients receiving i.v. vasodilators (e.g., nitrates, nitroprusside, nesiritide) at baseline: supine systolic blood pressure \< 120 mmHg.
3. Cardiogenic shock within the last 48 hours or evidence of volume depletion.
4. Ongoing myocardial ischaemia, coronary revascularisation procedure (PCI or CABG) during current admission or planned revascularisation.
5. ST-segment elevation myocardial infarction or administration of thrombolytic therapy.
6. Baseline creatinine ≥ 2.5 mg/dl (221 mmol/l).
7. Baseline hemoglobin \< 10 g/dl or a hematocrit \< 30%.
8. Hemodialysis, ultrafiltration or peritoneal dialysis within the last 7 days.
9. Heart failure due to active myocarditis, obstructive hypertrophic cardiomyopathy, congenital heart disease, restrictive cardiomyopathy or constrictive pericarditis. Heart failure caused by valvular disease.
10. Acute heart failure associated with uncontrolled hemodynamically relevant atrial fibrillation/flutter or ventricular rhythm disturbances.
11. Acute heart failure secondary to clinical evidence of digoxin toxicity or any other drug-related toxicity.
12. Significant chronic and/or acute lung disease that might interfere with the ability to interpret the dyspnea assessments or hemodynamic measurements (e.g., severe chronic obstructive pulmonary disease or acute pneumonia).
13. Mechanical circulatory or ventilatory support. Prior CPAP use is allowed, if discontinued at least 2 hours prior to study drug initiation.
14. Acute systemic infection/sepsis or other illness with a life expectancy less than 30 days.
15. Coronary artery bypass graft, or other cardiac surgery, or major non-cardiac surgery within the last 30 days.
16. Patients who received another investigational drug within 30 days prior to randomization.
17. Re-randomization in the current study.
18. Any factors that might interfere with the study conduct or interpretation of the results such as known drug or alcohol dependence.
19. Concomitant treatment with cyclosporin A or tacrolimus.

Primary outcomes:
measure: Incidence of death or worsening heart failure
timeFrame: 7 days following study drug initiation
Secondary outcomes:
measure: effect on patient's dyspnea assessment, measured using a visual analog scale
timeFrame: Over first 24 hours
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama-Birmingham
state: Alabama
city: Palo Alto
country: United States
facility: Advanced Heart Failure and Transplant Service, Palo Alto VA Health Care System, Cardiology Section
state: California
city: Denver
country: United States
facility: Denver VAMC
state: Colorado
city: Pittsburgh
country: United States
facility: The Heart Hospital at Alledgheny General, Division of Cardiology
state: Pennsylvania
city: Houston
country: United States
facility: Veterans Affairs Medical Center
state: Texas
city: Tyler
country: United States
facility: Tyler Cardiovascular Consultants
state: Texas
city: Danville
country: United States
facility: Danville Medical Center
state: Virginia
city: Bellevue
country: United States
facility: Medical Associates, Bellebue
state: Washington
city: Vienna
country: Austria
facility: AKH University of Vienna, Abt. Medizinische Kardiologie
city: Roskilde
country: Denmark
facility: Roskilde Amt Sygehus
city: Boulogne
country: France
facility: Hopital Ambroise Pare, Service de Cardiologie
city: Pontoise
country: France
facility: Heart Failure clinic C.H. Dubos
city: Strasbourg
country: France
facility: Hopitaux Universitaires de Strasbourg, Hopital Hautepierre
city: Toulouse
country: France
facility: CHU Rangueil, Cardiologie A
city: Aachen
country: Germany
facility: Medizinische Klinik I, Universitatsklinikum Aachen
city: Berlin
country: Germany
facility: Campus Virchow-Klinikum, Medizinishe Klinik mit Schwerpunkt Kardiologie
city: Gottingen
country: Germany
facility: Georg-August-Universitat Gottingen, Zentrum fur Innere Med
city: Athens
country: Greece
facility: Dept. of Cardiology, University of Athens, Alexandra Hospital
city: Ashkelon
country: Israel
facility: Barzilai Hospital
city: Haifa
country: Israel
facility: Carmel Medical Center
city: Holon
country: Israel
facility: Wolfson Medical Center
city: Jerusalem
country: Israel
facility: Hadassah Hospital
city: Nazareth
country: Israel
facility: Nazareth Hospital EMMS
city: Zerifin
country: Israel
facility: Assaf-Harofeh Medical Center
city: Bydgoszcz
country: Poland
facility: Klinika Kardiologii i Chorob Wewnetrznych, Samodzielny Publiczny Szpital
city: Gdansk
country: Poland
facility: Klinika Chorob Serca, Akademia Medyczna w Gdansku
city: Krakow
country: Poland
facility: I Klinika Kardiolgii, Collegium Medicum UJ
city: Krakow
country: Poland
facility: Institute of Cardiology College, College of Medicine of Jagellonian University
city: Wroclaw
country: Poland
facility: Kategra I Klinika Kardiolgii AM
city: Lausanne
country: Switzerland
facility: Centre Hospitalier Universitaire Vaudois (CHUV)
city: Lugano
country: Switzerland
facility: Cardio Centro Ticino, Servizio Cardiovasculare
city: Zurich
country: Switzerland
facility: University Hospital Zurich
city: Glasgow
country: United Kingdom
facility: Glasgow Royal Infirmary
city: Kingston Upon Hull
country: United Kingdom
facility: Hull Royal Infirmary
city: Scunthorpe
country: United Kingdom
facility: Scunthorpe General Hospital
Study officials:
References:
citation: Cotter G, Davison BA, Milo O, Bourge RC, Cleland JG, Jondeau G, Krum H, O'Connor CM, Metra M, Parker JD, Torre-Amione G, van Veldhuisen DJ, Kobrin I, Rainisio M, Senger S, Edwards C, McMurray JJ, Teerlink JR; VERITAS Investigators. Predictors and Associations With Outcomes of Length of Hospital Stay in Patients With Acute Heart Failure: Results From VERITAS. J Card Fail. 2016 Oct;22(10):815-22. doi: 10.1016/j.cardfail.2015.12.017. Epub 2015 Dec 22.
citation: McMurray JJ, Teerlink JR, Cotter G, Bourge RC, Cleland JG, Jondeau G, Krum H, Metra M, O'Connor CM, Parker JD, Torre-Amione G, van Veldhuisen DJ, Lewsey J, Frey A, Rainisio M, Kobrin I; VERITAS Investigators. Effects of tezosentan on symptoms and clinical outcomes in patients with acute heart failure: the VERITAS randomized controlled trials. JAMA. 2007 Nov 7;298(17):2009-19. doi: 10.1001/jama.298.17.2009.