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

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ClinicalTrials.gov Identifier: NCT00869115
Recruitment Status : Withdrawn (The study was not started due to a re-evaluation of the istaroxime development program)
First Posted : March 25, 2009
Last Update Posted : October 23, 2014
Sponsor:
Information provided by:
Debiopharm International SA

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

Condition or disease Intervention/treatment Phase
Heart Failure Drug: Istaroxime Phase 1

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.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: Randomized
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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 Start Date : June 2009

Resource links provided by the National Library of Medicine

Drug Information available for: Digoxin
U.S. FDA Resources

Arm Intervention/treatment
Experimental: 1
TREATMENT 0.5 μg/kg/min
Drug: Istaroxime
Istaroxime 0.5 μg/kg/min (30 μg/kg/h) continuous i.v. infusion for 24 hours
Experimental: 2
TREATMENT 1.0 μg/kg/min
Drug: Istaroxime
Istaroxime 1.0 μg/kg/min (60 μg/kg/h) continuous i.v. infusion for 24 hours
Experimental: 3
TREATMENT 1.5 μg/kg/min
Drug: Istaroxime
Istaroxime 1.5 μg/kg/min (90 μg/kg/h) continuous i.v. infusion for 24 hours
Placebo Comparator: 4
PLACEBO
Drug: Istaroxime
Placebo continuous i.v. infusion for 24 hours



Primary Outcome Measures :
  1. Pharmacokinetic endpoints : Istaroxime PK parameters: - Istaroxime and Istaroxime metabolites (PST2915/2922/3093) plasma concentrations - Istaroxime and Istaroxime metabolites (PST2915/2922/3093) urine concentrations
  2. Pharmacokinetic endpoints : Digoxin PK parameters: - Digoxin plasma concentrations
  3. 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
  4. Pharmacodynamic endpoints: - Change in echocardiographic parameters; - Change in SBP; - Change in non invasive cardiac output (Impedance cardiography) parameters.


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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Additional Information:
Publications:
Responsible Party: Hein Van Ingen, Medical Director, Debiopharm S.A.
ClinicalTrials.gov Identifier: NCT00869115     History of Changes
Other Study ID Numbers: Debio 0614-106
PAREXEL Study Number : 98378
First Posted: March 25, 2009    Key Record Dates
Last Update Posted: October 23, 2014
Last Verified: October 2014

Keywords provided by Debiopharm International SA:
Digoxin
Inotropes
Lusitropic agents
Istaroxime
Debio 0614

Additional relevant MeSH terms:
Heart Failure
Heart Diseases
Cardiovascular Diseases
Digoxin
Anti-Arrhythmia Agents
Cardiotonic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs