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

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

Detailed Description
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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.

Official Title
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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

Conditions
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Heart Failure

Intervention / Treatment
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* Drug: Istaroxime
* Drug: Istaroxime
* Drug: Istaroxime
* Drug: Istaroxime


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>TREATMENT 0.5 μg/kg/min | Drug: Istaroxime<br>* Istaroxime 0.5 μg/kg/min (30 μg/kg/h) continuous i.v. infusion for 24 hours<br>|
| Experimental: 2<br>TREATMENT 1.0 μg/kg/min | Drug: Istaroxime<br>* Istaroxime 1.0 μg/kg/min (60 μg/kg/h) continuous i.v. infusion for 24 hours<br>|
| Experimental: 3<br>TREATMENT 1.5 μg/kg/min | Drug: Istaroxime<br>* Istaroxime 1.5 μg/kg/min (90 μg/kg/h) continuous i.v. infusion for 24 hours<br>|
| Placebo Comparator: 4<br>PLACEBO | Drug: Istaroxime<br>* Placebo continuous i.v. infusion for 24 hours<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Digoxin, Inotropes, Lusitropic agents, Istaroxime, Debio 0614