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Levosimendan Efficacy Assessment by Cardiopulmonary Exercise Test (CPET)

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ClinicalTrials.gov Identifier: NCT02261948
Recruitment Status : Completed
First Posted : October 10, 2014
Results First Posted : November 6, 2015
Last Update Posted : November 6, 2015
Sponsor:
Collaborator:
Orion Corporation, Orion Pharma
Information provided by (Responsible Party):
Piergiuseppe Agostoni, Centro Cardiologico Monzino

Brief Summary:
The present study was conceived to evaluate the effects of levosimendan on cardiopulmonary exercise test (CPET) and DLCO ( Diffusion capacity of Lung for carbon monoxide) in patients with severe heart failure in stable clinical conditions (NYHA - New York Heart Association - class III, with a peak VO2 (Oxygen consumption ) < 12 ml/min/kg) on top of optimized standard therapy.

Condition or disease Intervention/treatment Phase
Heart Failure Drug: Levosimendan Drug: Placebo Phase 4

Detailed Description:

Eligible patients should have chronic HF (Heart Failure -class NYHA III or IV) in stable clinical conditions. Inclusion criteria were: left ejection fraction (EF) at echocardiography ≤35%, age ≥18 years old, peak VO2 <12 ml/min/kg measured by a CPET, a standard optimized therapy for HF that include ACE-inhibitors, ARBs (angiotensin II Receptor Blocker), aldosterone blocking agents (spironolactone), diuretics, and beta-blockers.

The exclusion criteria are: ongoing mechanical ventilation; recent or acute coronary syndromes; sustained ventricular tachycardia or ventricular fibrillation; severe aortic or mitral regurgitation, or known malfunctioning artificial heart valve; uncorrected obstructive valvular disease; hypertrophic obstructive cardiomyopathy; uncorrected thyroid disease.

Patients will be randomly assigned by means of prepared letters to the levosimendan or placebo group stratified by clinical centre in a 1:1 allocation using block randomization. The placebo infusion will be coloured identically to its respective active counterpart. Patients and investigators will be kept blinded to the treatment allocation for the entire duration of the trial. Study drug will be infused with an injection speed between 6 and 20 ml/min based on blood pressure, without a bolus, for 24 hours.

Medical history, physical examination and a blood sample examination will be recorded: NYHA class, BNP (Brain Natriuretic Peptide), haemoglobin, creatinine, blood urea nitrogen (BUN) will be recorded before and 24 hours after the drug infusion.

A two-dimensional standard echocardiography evaluation will be performed at the admission in the hospital.

A maximal CPET performed on a cycle ergometer (Sensor Medics Ergo 800S and V-max, Yorba-Linda, CA) with a personalized ramp aimed at achieving peak exercise in 10 minutes will be performed before and 24 hours after the drug infusion. Expiratory O2, CO2 (Carbon dioxide) and ventilation (VE) will be measured breath by breath. Peak VO2 (Carbon dioxide production) was considered to be the highest VO2 achieved during the exercise. A 12-lead electrocardiogram will be also recorded. Spirometry and DLCO measurements will be performed before ad 24-hours after the drug infusion. . DLCO will be measured by the single breath-constant expiratory flow technique

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 42 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Levosimendan Efficacy Assessment by Cardiopulmonary Exercise Test (CPET)
Study Start Date : September 2012
Actual Primary Completion Date : September 2014
Actual Study Completion Date : December 2014

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Levosimendan
Levosimendan must be diluted before the administration (500 ml of glucose). The intravenous infusion may be administered either by the peripheral or central. The dose and duration of therapy should be decided according to the patient's clinical condition and response to the drug. Treatment should be initiated with a loading dose of 6-12 mcg / kg infused over 10 minutes followed by a continuous infusion of 0.1 mcg / kg / min. A low infusion bolus (6 mcg / kg) is recommended for patients who have a concomitant intravenous treatment with vasodilators or inotropic. The patient's response should be evaluated during the infusion bolus or within 30 to 60 minutes and a dose adjustment based on clinical response.
Drug: Levosimendan
Treatment should be initiated with a loading dose of 6-12 mcg / kg infused over 10 minutes followed by a continuous infusion of 0.1 mcg / kg / min.
Other Name: SIMDAX

Placebo Comparator: Placebo
Placebo must be diluted before the administration (500 ml of glucose). The intravenous infusion may' be administered either by the peripheral or central. The dose and duration of therapy should be decided according to the patient's clinical condition and response to the drug. Treatment should be initiated with a loading dose of 6-12 mcg / kg infused over 10 minutes followed by a continuous infusion of 0.1 mcg / kg / min. A low infusion bolus (6 mcg / kg) is recommended for patients who have a concomitant intravenous treatment with vasodilators or inotropic. The patient's response should be evaluated during the infusion bolus or within 30 to 60 minutes and a dose adjustment based on clinical response.
Drug: Placebo
Treatment should be initiated with a loading dose of 6-12 mcg / kg infused over 10 minutes followed by a continuous infusion of 0.1 mcg / kg / min.




Primary Outcome Measures :
  1. Change in Peak VO2 (Oxygen Consumption ) [ Time Frame: 48 hours ]
    Primary endpoints: Levosimendan induced changes in peak VO2 (Oxygen consumption )


Secondary Outcome Measures :
  1. Changes in VE/VCO2 [ Time Frame: 48 hours ]
    Levosimendan induced changes on VE/VCO2 (VE: Expired Volume - VCO2: carbon dioxide production) relationship

  2. Change in DLCO (Diffusion Lung CO) [ Time Frame: 48 hours ]
    Levosimendan induced changes on DLCO ( Diffusion Lung CO). DLCO is measured by the single breath-constant expiratory flow technique (Sensor Medics 2200, Yorba Linda, CA) and we calculate also the DLCO adjusted for hemoglobin. Dilution of CH4 is used to measure alveolar volume.



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Ages Eligible for Study:   18 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • informed consent of the study signed
  • severe heart failure in stable clinical condition (NYHA class III, peak VO2 <12 ml / kg / min) in optimized medical therapy. The clinical stability is defined by the stability of the therapy, the weight and urine output for 3 days

Exclusion Criteria:

  • unstable patients from a clinical point of view, not in optimized therapy
  • patients unable to perform a CPET (Cardiopulmonary Exercise Test) .
  • are excluded from the protocol also patients with absolute contraindications to CPET (acute myocardial infarction, severe aortic stenosis, myocarditis or pericarditis, active, acute thromboembolism, sepsis,unstable angina, uncontrolled arrhythmia.
  • age < 18 years.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02261948


Locations
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Italy
Centro Cardiologico Monzino
Milano, MI, Italy, 20138
Sponsors and Collaborators
Centro Cardiologico Monzino
Orion Corporation, Orion Pharma
Investigators
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Principal Investigator: Piergiuseppe Agostoni, MD, PhD Centro Cardiologico Monzino,IRCCS
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Responsible Party: Piergiuseppe Agostoni, Professor, Centro Cardiologico Monzino
ClinicalTrials.gov Identifier: NCT02261948    
Other Study ID Numbers: CCFM 199/312
First Posted: October 10, 2014    Key Record Dates
Results First Posted: November 6, 2015
Last Update Posted: November 6, 2015
Last Verified: October 2015
Keywords provided by Piergiuseppe Agostoni, Centro Cardiologico Monzino:
Cardiac Failure
Severe Heart Failure
Additional relevant MeSH terms:
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Heart Failure
Heart Diseases
Cardiovascular Diseases
Simendan
Cardiotonic Agents
Vasodilator Agents
Phosphodiesterase 3 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs