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

NCT00616161 | Completed Phase 2 DMC

• 1 other identifier: PST2744-DM-04-012
• Study Type: interventional
• Target: 120
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Heart Failure

Keywords

Acute Heart Failure; Inotropes; Lusitropic agents; Istaroxime; PST2744

Outcome Measures

Primary Outcomes (1)

• To determine the minimum effective dose of ISTAROXIME by comparing the hemodynamic effect of 3 different doses of the drug versus placebo. Efficacy will be measured as a change in PCWP from right heart catheterization.

  6 hours drug infusion

Secondary Outcomes (1)

• safety, tolerability and efficacy on blood pressure, heart rate, cardiac index, stroke work index, right atrial pressure, systemic and pulmonary vascular resistances, Echocardiographic and Doppler parameters, neurohormonal parameters and renal function.

  6 and 24 hours after start of infusion

Study Arms (4)

1

EXPERIMENTAL

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

Drug: Istaroxime

2

EXPERIMENTAL

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

Drug: Istaroxime

3

EXPERIMENTAL

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

Drug: Istaroxime

4

PLACEBO COMPARATOR

Placebo iv infusion for six ours

Drug: Placebo

Interventions

Istaroxime DRUG

0.5 microgram/kg/min IV for 6 hours

Also known as: PST2744

1

Placebo DRUG

Placebo

Also known as: placebo of PST2744

4

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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%.

You may not qualify if:

• 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.

Sponsors & Collaborators

• sigma-tau i.f.r. S.p.A.: lead
• MDS Pharma Services: collaborator

Related Publications (10)

• 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.

  PMID: 17239700 BACKGROUND

• 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.

  PMID: 17239701 BACKGROUND

• 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.

  PMID: 17239702 BACKGROUND

• 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.

  PMID: 17239704 BACKGROUND

• 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.

  PMID: 17239705 BACKGROUND

• 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.

  PMID: 17729189 BACKGROUND

• 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.

  PMID: 12883318 BACKGROUND

• 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.

  PMID: 17113239 BACKGROUND

• 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.

  PMID: 19464414 DERIVED

• 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.

  PMID: 18534276 DERIVED

MeSH Terms

Conditions

Heart Failure

Interventions

Istaroxime

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Study Officials

• Mihai Gheorghiade, MD FACC

  Northwestern University Feinberg School of Medicine - Chicago

  STUDY CHAIR

• Witold Ruzyllo, MD

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

  PRINCIPAL INVESTIGATOR

• Cezar Macarie, MD

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

  PRINCIPAL INVESTIGATOR

• Dimitrios Th Kremastinos, MD

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

  PRINCIPAL INVESTIGATOR

• Serban I Bubenek-Turconi, MD

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

  PRINCIPAL INVESTIGATOR

• Maria Dorobantu, MD

  Emergency Hospital "Loreasca", Bucharest - ROMANIA

  PRINCIPAL INVESTIGATOR

• Jerzy Korewicki, MD

  National Institute of Cardiology, Warsaw, Poland

  PRINCIPAL INVESTIGATOR

• Jaroslaw Drodz, MD

  Hospital bieganskieko , Dept of Cardiology, Lodz - POLAND

  PRINCIPAL INVESTIGATOR

• Piotr Ponikowski, MD

  Iv Military Hospital, Wroclaw, POLAND

  PRINCIPAL INVESTIGATOR

• John N Nanas, MD PhD

  Alexandra University Hospital, Athens - GREECE

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY

Study Record Dates

• First Submitted: February 5, 2008
• First Posted: February 15, 2008
• Study Start: August 1, 2006
• Primary Completion: July 1, 2007
• Study Completion: August 1, 2007
• Last Updated: February 15, 2008

Record last verified: 2008-02