A Phase II Trial to Assess Hemodynamic Effects of Istaroxime in Pts With Worsening HF and Reduced LV Systolic Function (HORIZON-HF)
Primary Purpose
Heart Failure
Status
Completed
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
Istaroxime
Istaroxime
Istaroxime
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Heart Failure focused on measuring Acute Heart Failure, Inotropes, Lusitropic agents, Istaroxime, 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
Randomisation period inclusion criteria:
- 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.
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Experimental
Experimental
Experimental
Placebo Comparator
Arm Label
1
2
3
4
Arm Description
Istaroxime dose of 0.5 microgram/kg body weight/minute of iv infusion for six ours
Istaroxime dose of 1.0 microgram/kg body weight/minute of iv infusion for six ours
Istaroxime dose of 1.5 microgram/kg body weight/minute of iv infusion for six ours
Placebo iv infusion for six ours
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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.
Full Information
NCT ID
NCT00616161
First Posted
February 5, 2008
Last Updated
February 5, 2008
Sponsor
sigma-tau i.f.r. S.p.A.
Collaborators
MDS Pharma Services
1. Study Identification
Unique Protocol Identification Number
NCT00616161
Brief Title
A Phase II Trial to Assess Hemodynamic Effects of Istaroxime in Pts With Worsening HF and Reduced LV Systolic Function
Acronym
HORIZON-HF
Official Title
A Phase II Study to Assess the Hemodynamic Effects of Istaroxime, a Novel Lusinotropic Agent, in Patients Hospitalized With Worsening Heart Failure and a Reduced Left Ventricular Systolic Function
Study Type
Interventional
2. Study Status
Record Verification Date
February 2008
Overall Recruitment Status
Completed
Study Start Date
August 2006 (undefined)
Primary Completion Date
July 2007 (Actual)
Study Completion Date
August 2007 (Actual)
3. Sponsor/Collaborators
Name of the Sponsor
sigma-tau i.f.r. S.p.A.
Collaborators
MDS Pharma Services
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Heart Failure
Keywords
Acute Heart Failure, Inotropes, Lusitropic agents, Istaroxime, PST2744
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
120 (Actual)
8. Arms, Groups, and Interventions
Arm Title
1
Arm Type
Experimental
Arm Description
Istaroxime dose of 0.5 microgram/kg body weight/minute of iv infusion for six ours
Arm Title
2
Arm Type
Experimental
Arm Description
Istaroxime dose of 1.0 microgram/kg body weight/minute of iv infusion for six ours
Arm Title
3
Arm Type
Experimental
Arm Description
Istaroxime dose of 1.5 microgram/kg body weight/minute of iv infusion for six ours
Arm Title
4
Arm Type
Placebo Comparator
Arm Description
Placebo iv infusion for six ours
Intervention Type
Drug
Intervention Name(s)
Istaroxime
Other Intervention Name(s)
PST2744
Intervention Description
0.5 microgram/kg/min IV for 6 hours
Intervention Type
Drug
Intervention Name(s)
Istaroxime
Other Intervention Name(s)
PST2744
Intervention Description
1.0 microgram/kg/min IV for 6 hours
Intervention Type
Drug
Intervention Name(s)
Istaroxime
Other Intervention Name(s)
PST2744
Intervention Description
1.5 microgram/kg/min IV for 6 hours
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
placebo of PST2744
Intervention Description
Placebo
Primary Outcome Measure Information:
Title
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.
Time Frame
6 hours drug infusion
Secondary Outcome Measure Information:
Title
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.
Time Frame
6 and 24 hours after start of infusion
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
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
Randomisation period inclusion criteria:
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mihai Gheorghiade, MD FACC
Organizational Affiliation
Northwestern University Feinberg School of Medicine - Chicago
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Witold Ruzyllo, MD
Organizational Affiliation
National Institute of Cardiology, Department of Coronary Artery Disease - Warsaw - POLAND
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Cezar Macarie, MD
Organizational Affiliation
Insitutul de Boli Cardiovasculare C.C. Iliescu Bucuresti, Bucharest - ROMANIA
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Dimitrios Th Kremastinos, MD
Organizational Affiliation
Second Cardiology Department, Athens University Medical School, University Hospital Attikon, Athens - GREECE
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Serban I Bubenek-Turconi, MD
Organizational Affiliation
First Anaesth. & Intensive Care Dept., CC Iliescu Heart Disease Institute, Bucharest - ROMANIA
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Maria Dorobantu, MD
Organizational Affiliation
Emergency Hospital "Loreasca", Bucharest - ROMANIA
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Jerzy Korewicki, MD
Organizational Affiliation
National Institute of Cardiology, Warsaw, Poland
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Jaroslaw Drodz, MD
Organizational Affiliation
Hospital bieganskieko , Dept of Cardiology, Lodz - POLAND
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Piotr Ponikowski, MD
Organizational Affiliation
Iv Military Hospital, Wroclaw, POLAND
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
John N Nanas, MD PhD
Organizational Affiliation
Alexandra University Hospital, Athens - GREECE
Official's Role
Principal Investigator
12. IPD Sharing Statement
Citations:
PubMed Identifier
17239700
Citation
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.
Results Reference
background
PubMed Identifier
17239701
Citation
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.
Results Reference
background
PubMed Identifier
17239702
Citation
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.
Results Reference
background
PubMed Identifier
17239704
Citation
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.
Results Reference
background
PubMed Identifier
17239705
Citation
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.
Results Reference
background
PubMed Identifier
17729189
Citation
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.
Results Reference
background
PubMed Identifier
12883318
Citation
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.
Results Reference
background
PubMed Identifier
17113239
Citation
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.
Results Reference
background
PubMed Identifier
19464414
Citation
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.
Results Reference
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PubMed Identifier
18534276
Citation
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.
Results Reference
derived
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A Phase II Trial to Assess Hemodynamic Effects of Istaroxime in Pts With Worsening HF and Reduced LV Systolic Function
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