Phase I Interaction Study of Istaroxime and Digoxin in Subjects With Stable Heart Failure - Full Text View

Sponsor:	Debiopharm S.A.
Information provided by:	Debiopharm S.A.
ClinicalTrials.gov Identifier:	NCT00869115

Purpose

This study explores a potential drug-drug interaction between istaroxime and digoxin in patients with stable CHF on chronic oral digoxin treatment.

Condition	Intervention	Phase
Heart Failure	Drug: Istaroxime	Phase I

Study Type:	Interventional
Study Design:	Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Pharmacokinetics/Dynamics Study
Official Title:	A Randomized, Double-blind, Placebo-controlled Escalating Dose Phase I Interaction Study to Evaluate the Pharmacokinetics, Tolerability and Pharmacodynamics of Three Dose Levels of Debio 0614 (Istaroxime) as a 24-hour Constant Rate IV Infusion in Combination With Chronic Oral Digoxin Treatment in Patients With Controlled Cardiac Failure and Decreased Left Ventricular Systolic Function

Resource links provided by NLM:

MedlinePlus related topics: Heart Failure

Drug Information available for: Digoxin Istaroxime

U.S. FDA Resources

Further study details as provided by Debiopharm S.A.:

Primary Outcome Measures:

Pharmacokinetic endpoints : Istaroxime PK parameters: - Istaroxime and Istaroxime metabolites (PST2915/2922/3093) plasma concentrations - Istaroxime and Istaroxime metabolites (PST2915/2922/3093) urine concentrations [ Designated as safety issue: No ]
Pharmacokinetic endpoints : Digoxin PK parameters: - Digoxin plasma concentrations [ Designated as safety issue: No ]
Safety endpoints: - Incidence of adverse events; - Change in vital signs; - Change in 12-lead ECG parameters; - Incidence of clinically or hemodynamically significant episodes of supraventricular or ventricular arrhythmias detected by continuous EC [ Designated as safety issue: No ]
Pharmacodynamic endpoints: - Change in echocardiographic parameters; - Change in SBP; - Change in non invasive cardiac output (Impedance cardiography) parameters. [ Designated as safety issue: No ]

Estimated Enrollment:	48
Study Start Date:	June 2009

Arms	Assigned Interventions
1: Experimental TREATMENT 0.5 μg/kg/min	Drug: Istaroxime Istaroxime 0.5 μg/kg/min (30 μg/kg/h) continuous i.v. infusion for 24 hours
2: Experimental TREATMENT 1.0 μg/kg/min	Drug: Istaroxime Istaroxime 1.0 μg/kg/min (60 μg/kg/h) continuous i.v. infusion for 24 hours
3: Experimental TREATMENT 1.5 μg/kg/min	Drug: Istaroxime Istaroxime 1.5 μg/kg/min (90 μg/kg/h) continuous i.v. infusion for 24 hours
4: Placebo Comparator PLACEBO	Drug: Istaroxime Placebo continuous i.v. infusion for 24 hours

Detailed Description:

This is a single center, randomized, double blind, placebo controlled, escalating dose phase I interaction study. The three dose levels of istaroxime or placebo will be randomized sequentially to three cohorts (I to III) of 16 patients each (12 patients on istaroxime and 4 patients on placebo). Digoxin will be administered non blinded in all patients, once daily in the morning after a standardized breakfast, continuing with previously personalized dosage schedule during the screening period, treatment period, post treatment period and follow up period. Prior to accrual of cohorts II and III, a Data Monitoring Committee (DMC) will advise on the continuation to the next istaroxime dose, based on a predetermined safety review.

This 37 day study includes a screening period (Days -21 to -1), a treatment period (Day 1), a post treatment period (Days 2-4), and a follow up period (which includes one patient visit on Day 14). Patients will be confined in the phase I research center from Day -2 to Day 4.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Main screening inclusion criteria :

Signed informed consent;
Male or female patients ≥18 years;
Female patients of childbearing potential must not be pregnant;
Chronic stable cardiac function impairment (no change in heart failure medication over the last 3 months and without any dosage adjustment in the last 4 weeks);
Systolic blood pressure (SBP) of ≥ 90 mmHg and ≤ 140 mmHg;
LVEF ≤ 35% by any method (to be performed at screening if not measured within the last 12 months);
Chronic treatment (i.e. once daily dosing without interruption) with oral digoxin started at least 3 months prior to study entry and without any concomitant administration of other positive inotropic drugs;

Exclusion Criteria:

Main screening exclusion criteria :

Need for current or intermittent intravenous positive inotrope administration within the preceding 6 months, or hemodynamic support devices;
Acute coronary syndrome within the past 3 months;
Coronary artery bypass graft or percutaneous coronary intervention within the past 3 months;
Stroke within the past 6 months;
Atrial fibrillation or uncontrolled heart rate (HR) (> 100 beats per minute [bpm]);
Significant arrhythmia or second or third degree atrio-ventricular block;
Valvular disease as the primary cause of HF;
Significant ECG abnormalities as assessed by appropriately qualified physician or investigator including QTcF >450;
Positive testing for Human Immunodeficiency Virus (HIV), Hepatitis B and/or Hepatitis C;

Main randomization exclusion criteria:

HR > 100 bpm or < 50 bpm;
Serum potassium > 5.3 mmol/L or < 3.8 mmol/L and magnesium > 1.1 mmol/L or < 0.6 mmol/L,
TN I > ULN.

Contacts and Locations

No Contacts or Locations Provided

More Information

Additional Information:

Related Info This link exits the ClinicalTrials.gov site

Publications:

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. Epub 2008 Apr 9.

Responsible Party:	Debiopharm S.A. ( Hein Van Ingen, Medical Director )
Study ID Numbers:	Debio 0614-106, PAREXEL Study Number : 98378
Study First Received:	March 24, 2009
Last Updated:	November 2, 2009
ClinicalTrials.gov Identifier:	NCT00869115 History of Changes
Health Authority:	South Africa: Medicines Control Council; United States: Food and Drug Administration

Keywords provided by Debiopharm S.A.:

Digoxin
Inotropes
Lusitropic agents
Istaroxime
Debio 0614

Additional relevant MeSH terms:

Heart Failure
Heart Diseases
Molecular Mechanisms of Pharmacological Action
Cardiotonic Agents
Physiological Effects of Drugs
Enzyme Inhibitors
Cardiovascular Agents

Protective Agents
Pharmacologic Actions
Therapeutic Uses
Digoxin
Cardiovascular Diseases
Anti-Arrhythmia Agents

ClinicalTrials.gov processed this record on February 08, 2010