A Phase II Trial to Assess Hemodynamic Effects of Istaroxime in Pts With Worsening HF and Reduced LV Systolic Function

NCT ID: NCT00616161

Last Updated: 2008-02-15

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 120 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-08-31
• Study Completion Date: 2007-08-31

Brief Summary

The purpose of this study is to determine the minimum effective dose of Istaroxime, in patients requiring hospitalization for deterioration of chronic heart failure and left ventricular systolic dysfunction. This goal will be reached by comparing the hemodynamic effect of three different doses of the drug versus placebo. Efficacy will be measured as a change in Pulmonary Capillary Wedge Pressure from pre-infusion to the last assessment at six hours intravenous infusion.Secondary objectives will be to evaluate safety, tolerability and efficacy on other main hemodynamic parameters, echocardiographic and echo-doppler measurements, plus preliminary pharmacokinetics of the drug.

Detailed Description

Congestive heart failure is one of the most common cardiovascular conditions and it is presently reaching epidemic proportions. The prevalence of chronic heart failure has risen specifically as a result of the increased longevity and longer survival after myocardial infarction. In 2003, over one million hospitalization with a primary diagnosis of heart failure occurred in the United States of America, and a similar number has been reported in Europe, too. At present, approximately 5 million Americans are estimated to suffer of this syndrome and the number is expected to continue to increase with the increase and aging of the population. Despite advances in treatment, the mortality remains high in U.S.A. as in Europe, with nearly three hundred thousands patients dying of CHF as the primary or contributory cause each year.

The total number of hospital admissions approaches 3 million yearly when HF is listed as a primary or secondary diagnosis. Although these patients have a relatively low mortality during the hospitalization (less than 4%), the readmission rates within 60 days of discharge range from 20 to 30% and mortality within 60 days of discharge is 5 - 10%.

The primary aim of acute treatment of worsening CHF is to alleviate the symptoms of congestion and edema, improve the hemodynamic profile, and preserve renal function without causing myocardial injury. Improved hemodynamics usually results in relief of primary symptoms like dyspnea and edema and in a consequent improved sense of wellbeing and mental status. The improvement in hemodynamics may persist after the pharmacological interventions used in the acute phase are withdrawn.

The need in this setting is to decrease the filling pressures (RA pressure and PCWP), increase cardiac output, without increasing the heart rate and inducing/worsening atrial or ventricular arrhythmias. In addition, the agent should improve diastolic function, modulate the exaggerated neurohormonal responses to CHF and preserve/protect the viable but non contractile myocardium (e.g.: the hibernated myocardium). The agent should also facilitate the earlier start of life-saving therapies (e.g. beta - blockers).Pre-clinical data on Istaroxime show that this drug increases contractility without increasing heart rate and oxygen consumption; furthermore it is improving diastolic dysfunction and it not causing vasodilatation.

Conditions

Heart Failure

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

1

Istaroxime dose of 0.5 microgram/kg body weight/minute of iv infusion for six ours

Group Type: EXPERIMENTAL

Istaroxime

Intervention Type: DRUG

0.5 microgram/kg/min IV for 6 hours

2

Istaroxime dose of 1.0 microgram/kg body weight/minute of iv infusion for six ours

Group Type: EXPERIMENTAL

Istaroxime

Intervention Type: DRUG

1.0 microgram/kg/min IV for 6 hours

3

Istaroxime dose of 1.5 microgram/kg body weight/minute of iv infusion for six ours

Group Type: EXPERIMENTAL

Istaroxime

Intervention Type: DRUG

1.5 microgram/kg/min IV for 6 hours

4

Placebo iv infusion for six ours

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo

Interventions

Istaroxime

0.5 microgram/kg/min IV for 6 hours

Intervention Type: DRUG

Istaroxime

1.0 microgram/kg/min IV for 6 hours

Intervention Type: DRUG

Istaroxime

1.5 microgram/kg/min IV for 6 hours

Intervention Type: DRUG

Placebo

Placebo

Intervention Type: DRUG

Other Intervention Names

PST2744; PST2744; PST2744; placebo of PST2744

Eligibility Criteria

Inclusion Criteria

• Signing of a written informed consent form.
• Male or female patients aged between 18 and 85 years.
• Negative pregnancy test at screening, for women of childbearing potential.
• Body weight less or equal to 100 kg.
• Blood pressure not more than SAP=150 or DAP=90 mmHg.
• Heart rate in the range of 60-110 bpm
• Adequate Echo window available.
• Hospital admission to a monitored bed with a primary diagnosis of worsening of heart failure and LV Ejection Fraction less or equal to 35% documented by 2D-Echocardiogram, or radionuclide angiography or LV angiogram within 6 months prior to screening or at hospitalization.
• the clinical condition of the patient are stabilized within 48 hours from hospitalization and do not require continuous iv drug treatments
• no need for additional new oral treatments or any intravenous treatment administration over the following 8 hours is foreseen

• Any residual sign of heart failure (e.g.: Jugular Venous Distension, and/or Rales and/or Peripheral Oedema) associated with a PCWP more or equal to 20 mmHg,
• The last three consecutive determinations of PCWP, obtained during the stabilization period, have to be in a maximum range of variability of 10%.

Exclusion Criteria

• Ongoing treatment with oral or intravenous inotropes and/or inodilators.
• Patient treated with digoxin within the last week, can be randomised if the plasma concentration of digoxin are tested before randomisation and its value will be less than 0.5 ng/ml.
• Intermittent inotropes administration within 2 weeks.
• Symptoms of Heart Failure at randomization e.g.: dyspnoea
• Systolic blood pressure < 90 mmHg.
• Atrial fibrillation within 2 weeks.
• Left Ventricular Bundle Branch Block
• Cardiogenic shock or mechanical ventilation.
• Creatinine level > 3.0 mg/dl or requiring dialysis treatment.
• Left ventricular failure primarily from uncorrected obstructive valvular disease, hypertrophic obstructive cardiomyopathy, restrictive/obstructive cardiomyopathy, uncorrected thyroid disease, known acute myocarditis, known amyloid cardiomyopathy.
• Artificial heart valve.
• Electrical device implanted (ICD, CRT)
• Evidence of acute coronary syndrome within 3 months.
• History of stroke or transient ischemic attack in the 6 months prior to screening.
• History of sustained ventricular tachycardia.
• Coronary by-pass grafting or PTCA within the last 30 days
• INR > 1.5.
• Status post successful cardiac resuscitation.
• Serum K < 3.5 mEq/l or > 5.3 mEq/l just prior to treatment.
• ALT, AST > 3 times the upper normal limit just prior to treatment.
• Hemoglobin < 10 g/dl (either gender) just prior to treatment.
• Other clinically significant laboratory or medical conditions, which in the opinion of the Investigator make the patient unsuitable for evaluation in the study.
• Anticipated survival of less than 2 months for concomitant diseases.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

MDS Pharma Services

INDUSTRY

Sponsor Role: collaborator

sigma-tau i.f.r. S.p.A.

INDUSTRY

Sponsor Role: lead

Responsible Party

Northwestern University, Feinberg School of Medicine - 201 E. Huron - Chicago IL

Principal Investigators

Mihai Gheorghiade, MD FACC

Role: STUDY_CHAIR

Northwestern University Feinberg School of Medicine - Chicago

Witold Ruzyllo, MD

Role: PRINCIPAL_INVESTIGATOR

National Institute of Cardiology, Department of Coronary Artery Disease - Warsaw - POLAND

Cezar Macarie, MD

Role: PRINCIPAL_INVESTIGATOR

Insitutul de Boli Cardiovasculare C.C. Iliescu Bucuresti, Bucharest - ROMANIA

Dimitrios Th Kremastinos, MD

Role: PRINCIPAL_INVESTIGATOR

Second Cardiology Department, Athens University Medical School, University Hospital Attikon, Athens - GREECE

Serban I Bubenek-Turconi, MD

Role: PRINCIPAL_INVESTIGATOR

First Anaesth. & Intensive Care Dept., CC Iliescu Heart Disease Institute, Bucharest - ROMANIA

Maria Dorobantu, MD

Role: PRINCIPAL_INVESTIGATOR

Emergency Hospital "Loreasca", Bucharest - ROMANIA

Jerzy Korewicki, MD

Role: PRINCIPAL_INVESTIGATOR

National Institute of Cardiology, Warsaw, Poland

Jaroslaw Drodz, MD

Role: PRINCIPAL_INVESTIGATOR

Hospital bieganskieko , Dept of Cardiology, Lodz - POLAND

Piotr Ponikowski, MD

Role: PRINCIPAL_INVESTIGATOR

Iv Military Hospital, Wroclaw, POLAND

John N Nanas, MD PhD

Role: PRINCIPAL_INVESTIGATOR

Alexandra University Hospital, Athens - GREECE

References

Gheorghiade M, Sabbah HN. Istaroxime: an investigational luso-inotropic agent for acute heart failure syndromes. Am J Cardiol. 2007 Jan 22;99(2A):1A-3A. doi: 10.1016/j.amjcard.2006.09.001. Epub 2006 Sep 18. No abstract available.

Reference Type: BACKGROUND

PMID: 17239700 (View on PubMed)

Micheletti R, Palazzo F, Barassi P, Giacalone G, Ferrandi M, Schiavone A, Moro B, Parodi O, Ferrari P, Bianchi G. Istaroxime, a stimulator of sarcoplasmic reticulum calcium adenosine triphosphatase isoform 2a activity, as a novel therapeutic approach to heart failure. Am J Cardiol. 2007 Jan 22;99(2A):24A-32A. doi: 10.1016/j.amjcard.2006.09.003. Epub 2006 Sep 25.

Reference Type: BACKGROUND

PMID: 17239701 (View on PubMed)

Mattera GG, Lo Giudice P, Loi FM, Vanoli E, Gagnol JP, Borsini F, Carminati P. Istaroxime: a new luso-inotropic agent for heart failure. Am J Cardiol. 2007 Jan 22;99(2A):33A-40A. doi: 10.1016/j.amjcard.2006.09.004. Epub 2006 Sep 18.

Reference Type: BACKGROUND

PMID: 17239702 (View on PubMed)

Sabbah HN, Imai M, Cowart D, Amato A, Carminati P, Gheorghiade M. Hemodynamic properties of a new-generation positive luso-inotropic agent for the acute treatment of advanced heart failure. Am J Cardiol. 2007 Jan 22;99(2A):41A-46A. doi: 10.1016/j.amjcard.2006.09.005. Epub 2006 Sep 18.

Reference Type: BACKGROUND

PMID: 17239704 (View on PubMed)

Ghali JK, Smith WB, Torre-Amione G, Haynos W, Rayburn BK, Amato A, Zhang D, Cowart D, Valentini G, Carminati P, Gheorghiade M. A phase 1-2 dose-escalating study evaluating the safety and tolerability of istaroxime and specific effects on electrocardiographic and hemodynamic parameters in patients with chronic heart failure with reduced systolic function. Am J Cardiol. 2007 Jan 22;99(2A):47A-56A. doi: 10.1016/j.amjcard.2006.09.006. Epub 2006 Sep 20.

Reference Type: BACKGROUND

PMID: 17239705 (View on PubMed)

Wehrens XH. Istaroxime, a novel luso-inotropic agent for the treatment of acute heart failure. Curr Opin Investig Drugs. 2007 Sep;8(9):769-77.

Reference Type: BACKGROUND

PMID: 17729189 (View on PubMed)

Adamson PB, Vanoli E, Mattera GG, Germany R, Gagnol JP, Carminati P, Schwartz PJ. Hemodynamic effects of a new inotropic compound, PST-2744, in dogs with chronic ischemic heart failure. J Cardiovasc Pharmacol. 2003 Aug;42(2):169-73. doi: 10.1097/00005344-200308000-00003.

Reference Type: BACKGROUND

PMID: 12883318 (View on PubMed)

Ferrari P, Micheletti R, Valentini G, Bianchi G. Targeting SERCA2a as an innovative approach to the therapy of congestive heart failure. Med Hypotheses. 2007;68(5):1120-5. doi: 10.1016/j.mehy.2006.08.045. Epub 2006 Nov 17.

Reference Type: BACKGROUND

PMID: 17113239 (View on PubMed)

Shah SJ, Blair JE, Filippatos GS, Macarie C, Ruzyllo W, Korewicki J, Bubenek-Turconi SI, Ceracchi M, Bianchetti M, Carminati P, Kremastinos D, Grzybowski J, Valentini G, Sabbah HN, Gheorghiade M; HORIZON-HF Investigators. Effects of istaroxime on diastolic stiffness in acute heart failure syndromes: results from the Hemodynamic, Echocardiographic, and Neurohormonal Effects of Istaroxime, a Novel Intravenous Inotropic and Lusitropic Agent: a Randomized Controlled Trial in Patients Hospitalized with Heart Failure (HORIZON-HF) trial. Am Heart J. 2009 Jun;157(6):1035-41. doi: 10.1016/j.ahj.2009.03.007. Epub 2009 Apr 23.

Reference Type: DERIVED

PMID: 19464414 (View on PubMed)

Gheorghiade M, Blair JE, Filippatos GS, Macarie C, Ruzyllo W, Korewicki J, Bubenek-Turconi SI, Ceracchi M, Bianchetti M, Carminati P, Kremastinos D, Valentini G, Sabbah HN; HORIZON-HF Investigators. Hemodynamic, echocardiographic, and neurohormonal effects of istaroxime, a novel intravenous inotropic and lusitropic agent: a randomized controlled trial in patients hospitalized with heart failure. J Am Coll Cardiol. 2008 Jun 10;51(23):2276-85. doi: 10.1016/j.jacc.2008.03.015. Epub 2008 Apr 9.

Reference Type: DERIVED

PMID: 18534276 (View on PubMed)

Other Identifiers

PST2744-DM-04-012

Identifier Type: -

Identifier Source: org_study_id