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

Heart Failure Clinical Trial

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

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT00869115
• Other study ID #: Debio 0614-106
• Secondary ID: PAREXEL Study Nu
• Status: Withdrawn
• Phase: Phase 1
• First received: March 24, 2009
• Last updated: October 21, 2014
• Start date: June 2009

Study information

• Verified date: October 2014
• Source: Debiopharm International SA
• Contact: n/a
• Is FDA regulated: No
• Health authority: South Africa: Medicines Control CouncilUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Heart Failure

Intervention

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

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Debiopharm International SA

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Pharmacokinetic endpoints : Istaroxime PK parameters: - Istaroxime and Istaroxime metabolites (PST2915/2922/3093) plasma concentrations - Istaroxime and Istaroxime metabolites (PST2915/2922/3093) urine concentrations			No
Primary	Pharmacokinetic endpoints : Digoxin PK parameters: - Digoxin plasma concentrations			No
Primary	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			No
Primary	Pharmacodynamic endpoints: - Change in echocardiographic parameters; - Change in SBP; - Change in non invasive cardiac output (Impedance cardiography) parameters.			No

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