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

February 5, 2008 updated by: sigma-tau i.f.r. S.p.A.

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

120

Phase

  • Phase 2

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 85 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: 1
Istaroxime dose of 0.5 microgram/kg body weight/minute of iv infusion for six ours
Drug: Istaroxime
0.5 microgram/kg/min IV for 6 hours
Other Names:
  • PST2744
Drug: Istaroxime
1.0 microgram/kg/min IV for 6 hours
Other Names:
  • PST2744
Drug: Istaroxime
1.5 microgram/kg/min IV for 6 hours
Other Names:
  • PST2744
Experimental: 2
Istaroxime dose of 1.0 microgram/kg body weight/minute of iv infusion for six ours
Drug: Istaroxime
0.5 microgram/kg/min IV for 6 hours
Other Names:
  • PST2744
Drug: Istaroxime
1.0 microgram/kg/min IV for 6 hours
Other Names:
  • PST2744
Drug: Istaroxime
1.5 microgram/kg/min IV for 6 hours
Other Names:
  • PST2744
Experimental: 3
Istaroxime dose of 1.5 microgram/kg body weight/minute of iv infusion for six ours
Drug: Istaroxime
0.5 microgram/kg/min IV for 6 hours
Other Names:
  • PST2744
Drug: Istaroxime
1.0 microgram/kg/min IV for 6 hours
Other Names:
  • PST2744
Drug: Istaroxime
1.5 microgram/kg/min IV for 6 hours
Other Names:
  • PST2744
Placebo Comparator: 4
Placebo iv infusion for six ours
Drug: Placebo
Placebo
Other Names:
  • placebo of PST2744

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
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
6 hours drug infusion

Secondary Outcome Measures

Outcome Measure
Time Frame
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
6 and 24 hours after start of infusion

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

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

Collaborators

MDS Pharma Services

Investigators

  • Study Chair: Mihai Gheorghiade, MD FACC, Northwestern University Feinberg School of Medicine - Chicago
  • Principal Investigator: 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, 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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

August 1, 2006

Primary Completion (Actual)

July 1, 2007

Study Completion (Actual)

August 1, 2007

Study Registration Dates

First Submitted

February 5, 2008

First Submitted That Met QC Criteria

February 5, 2008

First Posted (Estimate)

February 15, 2008

Study Record Updates

Last Update Posted (Estimate)

February 15, 2008

Last Update Submitted That Met QC Criteria

February 5, 2008

Last Verified

February 1, 2008

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PST2744-DM-04-012

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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