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Withdrawn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
Istaroxime
Istaroxime
Istaroxime
Sponsored by
About this trial
This is an interventional treatment trial for Heart Failure focused on measuring Digoxin, Inotropes, Lusitropic agents, Istaroxime, Debio 0614
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.
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Experimental
Experimental
Experimental
Placebo Comparator
Arm Label
1
2
3
4
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
1
Arm Type
Experimental
Arm Description
TREATMENT 0.5 μg/kg/min
Arm Title
2
Arm Type
Experimental
Arm Description
TREATMENT 1.0 μg/kg/min
Arm Title
3
Arm Type
Experimental
Arm Description
TREATMENT 1.5 μg/kg/min
Arm Title
4
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 : Istaroxime PK parameters: - Istaroxime and Istaroxime metabolites (PST2915/2922/3093) plasma concentrations - Istaroxime and Istaroxime metabolites (PST2915/2922/3093) urine concentrations
Title
Pharmacokinetic endpoints : Digoxin PK parameters: - Digoxin plasma concentrations
Title
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
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
No
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
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Phase I Interaction Study of Istaroxime and Digoxin in Subjects With Stable Heart Failure
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