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

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

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

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.

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.