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

Primary Purpose

Heart Failure

Status

Withdrawn

Phase

Phase 1

Locations

Study Type

Interventional

Intervention

Istaroxime

About this trial

This is an interventional treatment trial for Heart Failure focused on measuring Digoxin, Inotropes, Lusitropic agents, Istaroxime, Debio 0614

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Placebo Comparator

Arm Label

Arm Description

TREATMENT 0.5 μg/kg/min

TREATMENT 1.0 μg/kg/min

TREATMENT 1.5 μg/kg/min

PLACEBO

Outcomes

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

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.

Secondary Outcome Measures

Full Information

NCT ID

NCT00869115

First Posted

March 24, 2009

Last Updated

October 21, 2014

Sponsor

Debiopharm International SA

1. Study Identification

Unique Protocol Identification Number

NCT00869115

Brief Title

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

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

Study Type

Interventional

2. Study Status

Record Verification Date

October 2014

Overall Recruitment Status

Withdrawn

Why Stopped

The study was not started due to a re-evaluation of the istaroxime development program

Study Start Date

June 2009 (undefined)

Primary Completion Date

undefined (undefined)

Study Completion Date

undefined (undefined)

3. Sponsor/Collaborators

Name of the Sponsor

Debiopharm International SA

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Heart Failure

Keywords

Digoxin, Inotropes, Lusitropic agents, Istaroxime, Debio 0614

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

0 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm Type

Experimental

Arm Description

TREATMENT 0.5 μg/kg/min

Arm Title

Arm Type

Experimental

Arm Description

TREATMENT 1.0 μg/kg/min

Arm Title

Arm Type

Experimental

Arm Description

TREATMENT 1.5 μg/kg/min

Arm Title

Arm Type

Placebo Comparator

Arm Description

PLACEBO

Intervention Type

Drug

Intervention Name(s)

Istaroxime

Intervention Description

Istaroxime 0.5 μg/kg/min (30 μg/kg/h) continuous i.v. infusion for 24 hours

Intervention Type

Drug

Intervention Name(s)

Istaroxime

Intervention Description

Istaroxime 1.0 μg/kg/min (60 μg/kg/h) continuous i.v. infusion for 24 hours

Intervention Type

Drug

Intervention Name(s)

Istaroxime

Intervention Description

Istaroxime 1.5 μg/kg/min (90 μg/kg/h) continuous i.v. infusion for 24 hours

Intervention Type

Drug

Intervention Name(s)

Istaroxime

Intervention Description

Placebo continuous i.v. infusion for 24 hours

Primary Outcome Measure Information:

Title

Pharmacokinetic endpoints : Digoxin PK parameters: - Digoxin plasma concentrations

Title

Pharmacodynamic endpoints: - Change in echocardiographic parameters; - Change in SBP; - Change in non invasive cardiac output (Impedance cardiography) parameters.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility 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.

12. IPD Sharing Statement

Citations:

PubMed Identifier

18534276

Citation

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.

Results Reference

background

Links:

URL

http://www.debiopharm.com

Description

Related Info

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

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