Phase I Interaction Study of Istaroxime and Digoxin in Subjects With Stable Heart Failure

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.

• Istaroxime (Drug): Istaroxime 0.5 μg/kg/min (30 μg/kg/h) continuous i.v. infusion for 24 hours
• Istaroxime (Drug): Istaroxime 1.0 μg/kg/min (60 μg/kg/h) continuous i.v. infusion for 24 hours
• Istaroxime (Drug): Istaroxime 1.5 μg/kg/min (90 μg/kg/h) continuous i.v. infusion for 24 hours
• Istaroxime (Drug): Placebo continuous i.v. infusion for 24 hours

Primary outcomes

• Pharmacokinetic endpoints : Istaroxime PK parameters: - Istaroxime and Istaroxime metabolites (PST2915/2922/3093) plasma concentrations - Istaroxime and Istaroxime metabolites (PST2915/2922/3093) urine concentrations
• Pharmacokinetic endpoints : Digoxin PK parameters: - Digoxin plasma concentrations
• 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
• Pharmacodynamic endpoints: - Change in echocardiographic parameters; - Change in SBP; - Change in non invasive cardiac output (Impedance cardiography) parameters.

Sex: All, ages: 18 Years to any

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.

• 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