Clinical trial NCT00524433: Tezosentan in the Treatment of 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
acute decompensation of chronic heart failure
new onset of heart failure
tezosentan
Actelion
Lead sponsor: Idorsia Pharmaceuticals Ltd.
Sponsor class: INDUSTRY
First posted: 2007-09-03
Enrollment: 713
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: within 7 days following study drug initiation
Secondary outcomes:
measure: Patient's dyspnea assessment, measured using a visual analog scale
timeFrame: Over first 24 hours
Other outcomes:
Locations:
city: Huntsville
country: United States
facility: Oracle Research
state: Alabama
city: Los Angeles
country: United States
facility: USC Medical Center
state: California
city: Jacksonville
country: United States
facility: Jacksonville Center for Clinical Research
state: Florida
city: Miami
country: United States
facility: University of Miami-Jackson Memorial Hospital
state: Florida
city: Augusta
country: United States
facility: University Hospital
state: Georgia
city: Iowa City
country: United States
facility: University of Iowa Hospital and Clinics
state: Iowa
city: Slidell
country: United States
facility: Medical Research Institute
state: Louisiana
city: Springfield
country: United States
facility: Baystate Medical Center-Cardiology Section
state: Massachusetts
city: Elmhurst
country: United States
facility: Elmhurst Hospital Center
state: New York
city: New York
country: United States
facility: Columbia Presbyterian Medical Center-Heart Failure Center
state: New York
city: New York
country: United States
facility: New York University School of Medicine
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Greensboro
country: United States
facility: LeBauer Cardiovascular Research Foundation
state: North Carolina
city: Houston
country: United States
facility: Baylor College of Medicine - Texas Medical Center
state: Texas
city: Houston
country: United States
facility: University of Texas, MD Anderson Cancer Center
state: Texas
city: Prahran
country: Australia
facility: Alfred Hospital, Monash University, Central and Eastern School
state: Victoria
city: Concord NSW
country: Australia
facility: Concord Repatriation Hospital
city: Woodville SA
country: Australia
facility: Queen Elizabeth Hospital
city: Brno
country: Czechia
facility: Faculty Hospital St. Anna
city: Liberec
country: Czechia
facility: Krajska Nemocnice Liberec
city: Prague
country: Czechia
facility: Klinika Kardiologie IKEM
city: Prague
country: Czechia
facility: University Hospital Vinohrady (FNKV)
city: Usti nad Labem
country: Czechia
facility: Masaryk Hospital
city: Berlin
country: Germany
facility: Universitatsklinikum der Humboldt-Universitat Berlin, Campus Charite Mitte, Med. Klinik und Poliklinik, Kardiologie
city: Greifswald
country: Germany
facility: Universitat Greifswald, Klinik fur Innere Medizin B
city: Langen
country: Germany
facility: Asklepios Klinik Langen, Abteilung fur Innere Medizin
city: Lubeck
country: Germany
facility: Universitatsklinikum Schleswig Holstein, Medizinische Klinik II, Kardiologie
city: Regensburg
country: Germany
facility: Klinik u. Poliklinik F. Inn. Med. II, Univ. Klinik Regensburg
city: Budapest
country: Hungary
facility: Jahn Ferenc, Delpesti Korhaz
city: Budapest
country: Hungary
facility: Polyclinic of the Hospitaler Brothers of St. John of God
city: Debrecen
country: Hungary
facility: University of Debrecen
city: Szeged
country: Hungary
facility: 2nd Department of Medicine & Cardiology Centre
city: Brescia
country: Italy
facility: Cattedra di Cardiologia, c/o Spedali Civili
city: Rozzano (MI)
country: Italy
facility: Istituto Clinico Humanitas, U.O. Cardiologia Clin. E Insuff. Cardiaca
city: Alesund
country: Norway
facility: Sentralsykehuset i More og Romsdal, Dept. of Cardiology
city: Oslo
country: Norway
facility: Aker University Hospital, Div. Cardiology
city: Stavanger
country: Norway
facility: Central Hospital in Rogaland, Cardiology Division
city: Birmingham
country: United Kingdom
facility: University Department of Medicine, City Hospital
city: Bridlington
country: United Kingdom
facility: Cardiology Department, Bridlington & District Hospital
city: Glasgow
country: United Kingdom
facility: University of Glasgow West
city: Leicester
country: United Kingdom
facility: Dept. of Medicine & Therapeutics, University of Leicester
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.