ELEVATE Early LEvosimendan Vs Usual Care in Advanced Chronic hearT failurE

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by Niguarda Hospital
Sponsor:
Collaborator:
Orion Corporation, Orion Pharma
Information provided by (Responsible Party):
Niguarda Hospital
ClinicalTrials.gov Identifier:
NCT01290146
First received: February 3, 2011
Last updated: June 9, 2014
Last verified: June 2014
  Purpose

The purpose of this study is to compare in patients with Advanced Chronic Heart Failure the effects of Levosimendan versus diuretic (single 24-hour infusion) applied at the early detection of impending destabilization on hospitalization-free survival during 12 months.

Patients with advanced chronic heart failure (ACHF) have a short term reduced life expectancy with recurrent hospital admissions for clinical exacerbations. Levosimendan improves contractility by calcium-dependent binding to troponin C, determines vasodilation of the coronary arteries and systemic resistance vessels, thus decreasing preload and afterload, while exerting a protective effect on the myocardium against ischemia-reperfusion damage. In randomized clinical trials of acute heart failure patients, levosimendan improved hemodynamics and patients' quality of life and decreased natriuretic peptide plasma levels, with no excess mortality The study will assess whether the administration of levosimendan (single 24-hour infusion) at the early detection of deterioration may reduce frequency and duration of hospital admissions, improve functional status and quality of life in ACHF patients, with respect to diuretic infusion.


Condition Intervention Phase
Advanced Chronic Heart Failure
Drug: Diuretics
Drug: Levosimendan
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Subject)
Primary Purpose: Treatment
Official Title: Early Use of Levosimendan Compared to Usual Care in Advanced Chronic Heart Failure (ACHF)

Resource links provided by NLM:


Further study details as provided by Niguarda Hospital:

Primary Outcome Measures:
  • Number of days alive free of Transplant and out-of-hospital (DAOH) [ Time Frame: Measured at 12 months ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Incidence of acute renal dysfunction [ Time Frame: Measured at at 24 hours since inception of randomized treatment for acute worsening HF ] [ Designated as safety issue: Yes ]
    proportion of subjects who develop AKIN stage 1 (increase > 0.3 mg/dl or > 25% in serum creatinine from previous visit)

  • All cause mortality, hospital readmission and unscheduled office and emergency department visits for ADCHF [ Time Frame: Measured at 12 months ] [ Designated as safety issue: Yes ]
    A combination of all cause hospital admissions/death/urgent heart transplantation/LV assist device implantation

  • BNP changes [ Time Frame: Measured at at end-of- study and at each eventual destabilization ] [ Designated as safety issue: No ]
    Percent changes in BNP vs baseline

  • Number of hospital admissions for acute worsening HF [ Time Frame: Measured at 12 months ] [ Designated as safety issue: Yes ]
    Number of hospital admissions for acute worsening HF

  • Costs [ Time Frame: Measured at 12 months ] [ Designated as safety issue: No ]
    Direct health care costs for days in hospital, supplementary visits, drug treatment

  • Treatment-related adverse events [ Time Frame: Measured at 12 months ] [ Designated as safety issue: Yes ]
    death, hospital a dimission, emergency room or clinic unscheduled visits

  • Adverse changes in blood pressure or heart rate [ Time Frame: Measured at 24 hours after iv treatment ] [ Designated as safety issue: Yes ]
    Hypotension (< 90 mmHg), tachycardia (> 110 bpm)

  • ECG changes [ Time Frame: Measured at 24 hours after iv treatment ] [ Designated as safety issue: Yes ]
    Rhythm, rate, conduction disturbances, ventricular arrhythmias, repolarization changes


Estimated Enrollment: 134
Study Start Date: February 2011
Estimated Study Completion Date: May 2015
Estimated Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Diuretics
Patients randomized to diuretics receive a 24-hour diuretic infusion with a maximum cumulative dose up to 200 mg furosemide/24 h
Drug: Diuretics
Patients randomized to diuretics receive a 24-hour diuretic infusion with a maximum cumulative dose up to 200 mg furosemide/24 h
Experimental: Levosimendan

Patients randomized to Levosimendan receive a 24-hour levosimendan infusion with NO prior bolus injection.

Starting doses will be based on baseline SBP levels

  • SBP ≥ 85-99mmHg: 0.05 mcg/kg/min
  • SBP ≥100 mmHg: 0.1 mcg/kg/min
Drug: Levosimendan

Patients randomized to Levosimendan receive a 24-hour levosimendan infusion with NO prior bolus injection.

Starting doses will be based on baseline SBP levels

  • SBP ≥ 85-99mmHg: 0.05 mcg/kg/min
  • SBP ≥100 mmHg: 0.1 mcg/kg/min

Detailed Description:

BACKGROUND Patients with advanced chronic heart failure (ACHF) have a short term reduced life expectancy with recurrent hospital admissions for clinical exacerbations. ACHF poses a heavy burden to cardiology departments, where these patients are referred for the severity of their clinical condition, which require a specialist approach, and results in high health care costs due to frequent rehospitalizations.

Patients with ACHF ≥ 2 hospital admissions in 6 months are at high risk of recurrent exacerbations. The benefits of strict outpatient follow-up at specialised HF vs standard community care in ACHF patients have been consistently demonstrated. The standard approach at HF clinics is based on flexible diuretic dose and outpatient iv diuretics as bolus or infusion at early signs of decompensation. Although this strategy results in symptomatic benefit and prevents approximately one third of hospital admission for acute exacerbations, a relevant proportion of patients will still need hospitalization. Predictors of lack of benefit are low systolic blood pressure, prior increase in oral diuretics and beta-blocker use, which taken together represent markers of severe disease susceptible to evolve in a low output state.

In the HF clinic setting, a novel strategy for these patients, to include early support to myocardial contractility, i.e. before compelling criteria for hospital admission become manifest, might prevent further prolonged hospitalizations, myocardial damage and impairment in renal function TRIAL RATIONALE Levosimendan improved hemodynamics and patients' quality of life and decreased natriuretic peptide plasma levels, with no excess mortality, in randomized clinical trials of acute heart failure. In SURVIVE an early larger treatment effect of levosimendan was apparent in patients with acute worsening of chronic HF treatment than in those with de novo disease, possibly because a greater proportion of these patients may be on beta-blockers, that are known to interfere with dobutamine or may potentiate the circulatory actions of levosimendan. Thus levosimendan may be unattractive first-line agent in destabilized ACHF patients on beta-blockers.

Based on the drug cardioprotective properties, hemodynamic and neurohormonal effects, we propose a novel therapeutic approach for the clinically-driven use of levosimendan in recurrent acute exacerbations of ACHF.

Dosing of the drug will omit the bolus to increase tolerability in this severely ill patient population.

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Written informed consent
  • Systolic dysfunction (LVEF ≤ 35% by echo assessment within 6 months before enrolment)
  • No requirement for hospital admission for diagnostic work up or elective treatment to define etiology and/or treatment plan
  • Already on optimal standard HF treatment based on individual tolerance, including cardiac resynchronization therapy (CRT)/ICD device according to current guidelines
  • At least 2 hospital admissions for HF in the 6 months before enrolment, the most recent one within 30-90 days before enrolment with requirement for inotrope administration

Exclusion Criteria:

  • Participant in other studies in the last 30 days
  • Life expectancy < 1 year for comorbid conditions other than HF
  • Pregnancy, lactation, childbearing potential unless on adequate contraception
  • Acute coronary syndromes, percutaneous or surgical revascularization, valve surgery performed within 8 weeks before enrolment
  • Planned percutaneous or surgical procedures (except for heart transplantation)
  • CRT within 6 months before enrolment
  • Cardiogenic shock
  • Supine systolic BP < 85 mmHg
  • Severe liver insufficiency (>three-fold increase in AST-ALT )
  • Sever chronic kidney dysfunction (estimated GFR < 30 ml/min)
  • Sustained ventricular tachycardia
  • Severe chronic or current acute infection (temperature >38 C, WBC >15,000/mm3)
  • Severe chronic obstructive pulmonary disease (FEV1 <30% predicted or on oxygen therapy)
  • Severe persistent anemia (Hb < 10 g/l))
  • ACHF exacerbation due to conditions requiring specific treatment (e.g. anemia, atrial fibrillation, supraventricular tachycardia ) Documented low compliance or unavailable for programmed follow-up visits and phone contact
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01290146

Contacts
Contact: Renata De Maria, MD +39 02 6610 ext 1344 renata_de_maria@hotmail.com

Locations
Italy
Fondazione S. Maugeri. IRCCS Istituto di Cassano Murge Not yet recruiting
Cassano Murge, Bari, Italy, 70020
Contact: Rocco Lagioia, MD       rocco.lagioia@fsm.it   
Principal Investigator: Rocco Lagioia, MD         
Ospedali Riuniti di Ancona Cardiology Presidio Lancisi Not yet recruiting
Ancona, Italy, 60020
Contact: Gianpiero Perna, MD       gp.perna@ospedaliriuniti.marche.it   
Principal Investigator: Gianpiero Perna, MD         
Azienda Ospedaliero-Universitaria, Consorziale Policlinico di Bari, U.O. Cardiologia Universitaria, Dipartimento Emergenza e Trapianti di Organi Not yet recruiting
Bari, Italy
Contact: Stefano Favale, MD         
Principal Investigator: Stefano Favale, MD         
Ospedali Riuniti di Bergamo Cardiovascular Medicine Recruiting
Bergamo, Italy, 24128
Contact: Michele Senni, MD       msenni@ospedaliriuniti.bergamo.it   
Principal Investigator: Michele Senni, MD         
Ospedale Brotzu Cardiology Not yet recruiting
Cagliari, Italy, 09134
Contact: Maurizio Porcu, MD       maurizioporcu@aob.it   
Principal Investigator: Maurizio Porcu, MD         
Ospedale Sant'Anna Cardiology Not yet recruiting
Como, Italy, 22100
Contact: Carlo Campana, MD       carlo.campana@hsacomo.org   
Principal Investigator: Carlo Campana, MD         
Ospedale SS Annunziata Cardiology Not yet recruiting
Cosenza, Italy, 87100
Contact: Gianfranco Misuraca, MD       gianfranco.misuraca@gmail.com   
Principal Investigator: Gianfranco Misuraca, MD         
Istituti Ospitalieri di Cremona Cardiology Recruiting
Cremona, Italy, 26100
Contact: Salvatore Pirelli, MD       cardio.aioc@e-cremona.it   
Principal Investigator: Salvatore Pirelli, MD         
Ospedale Santa Maria Nuova Cardiology Not yet recruiting
Firenze, Italy, 50100
Contact: Massimo Milli, MD       massimo.milli@asf.toscana.it   
Principal Investigator: Massimo Milli, MD         
Ospedale Vito Fazzi Recruiting
Lecce, Italy, 73199
Contact: Giovanni Milanese, MD       milagio@inwind.it   
Principal Investigator: Giovanni Milanese, MD         
Azienda Ospedaliera Niguarda Heart Failure and Heart Transplant Program Recruiting
Milan, Italy, 20162
Contact: Fabrizio Oliva, MD       fabrizio.oliva@ospedaleniguarda.it   
Principal Investigator: Fabrizio Oliva, MD         
Istituto Auxologico Italiano - IRCCS Clinical Cardiology Cardiovascular Department Not yet recruiting
Milan, Italy, 20148
Contact: Gabriella Malfatto, md       malfii@auxologico.it   
Principal Investigator: Gabriella Malfatto, MD         
Gruppo Policlinico di Monza Clinical Cardiology and Heart Failure Unit Cardiology Department Not yet recruiting
Monza, Italy, 20052
Contact: Andrea Mortara, MD       andreamortara@libero.it   
Principal Investigator: Andrea Mortara, MD         
Azienda Ospedaliera S. Gerardo Hear Failure and Cardiomyopathy Clinic Not yet recruiting
Monza, Italy, 20052
Contact: Antonio Cirò, MD       unitascompenso@hsgerardo.org   
Principal Investigator: Antonio Cirò, MD         
Ospedale Santa Maria della Misericordia Cardiology Recruiting
Perugia, Italy, 06156
Contact: Gianfranco Alunni, MD       gianfranco.alunni1@tin.it   
Principal Investigator: Gianfranco Alunni, MD         
Ospedale Guglielmo da Saliceto Cardiology Department Not yet recruiting
Piacenza, Italy, 29100
Contact: Massimo Piepoli, MD       m.piepoli@ausl.pc.it   
Principal Investigator: Massimo Piepoli, MD         
Azienda Ospedaliera San Giovanni- Addolorata 1st Cardiology Unit Recruiting
Roma, Italy, 00184
Contact: Alessandro Boccanelli, MD       aboccanelli@hsangiovanni.roma.it   
Principal Investigator: Alessandro Boccanelli, MD         
Università di Roma Sapienza Dipartimento di Scienze Cardiovascolari e Respiratorie Not yet recruiting
Roma, Italy, 00161
Contact: Francesco Fedele, MD       Francesco.Fedele@uniroma1.it   
Principal Investigator: Francesco Fedele, MD         
Azienda Ospedaliera San Camillo-Forlanini, Cardiology, Heart Failure Clinic Not yet recruiting
Roma, Italy, 00151
Contact: Giovanni Pulignano, MD       gipulig@yahoo.it   
Principal Investigator: Giovanni Pulignano, MD         
Ospedale Santo Spirito, Cardiology Not yet recruiting
Roma, Italy, 00193
Contact: Angela Beatrice Scardovi, MD       angela.scardovi@asl-rme.it   
Principal Investigator: Angela Beatrice Scardovi, MD         
Azienda Ospedaliero-Universitaria, Ospedale di Cattinara Cardiology Recruiting
Trieste, Italy, 34149
Contact: Francesco Lo Giudice, MD       francescolog67@gmail.com   
Principal Investigator: Francesco Lo Giudice, MD         
Ospedale di Circolo e Fondazione Macchi Cardiology Not yet recruiting
Varese, Italy, 21100
Contact: Fabrizio Morandi, MD       fabrimora@libero.it   
Principal Investigator: Fabrizio Morandi, MD         
Sponsors and Collaborators
Niguarda Hospital
Orion Corporation, Orion Pharma
Investigators
Study Chair: Fabrizio Oliva, MD Heart Failure Heart Transplant Program, Cardiovascular Department, Niguarda Hospital, Milan, Italy
Study Chair: Michele Senni, MD Cardiovascular Medicine Ospedali Riuniti, Bergamo, Italy
  More Information

No publications provided

Responsible Party: Niguarda Hospital
ClinicalTrials.gov Identifier: NCT01290146     History of Changes
Other Study ID Numbers: EudraCT code 2009-016958-41, FO002
Study First Received: February 3, 2011
Last Updated: June 9, 2014
Health Authority: Italy: The Italian Medicines Agency

Keywords provided by Niguarda Hospital:
Heart Failure
Levosimendan
Inotropic agents
Phosphodiesterase Inhibitors
Vasodilators
Diuretics

Additional relevant MeSH terms:
Heart Failure
Heart Diseases
Cardiovascular Diseases
Diuretics
Simendan
Natriuretic Agents
Physiological Effects of Drugs
Pharmacologic Actions
Anti-Arrhythmia Agents
Cardiovascular Agents
Therapeutic Uses
Cardiotonic Agents
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Vasodilator Agents
Protective Agents

ClinicalTrials.gov processed this record on September 30, 2014