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

Information source: Debiopharm International SA
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Heart Failure

Intervention: Istaroxime (Drug); Istaroxime (Drug); Istaroxime (Drug); Istaroxime (Drug)

Phase: Phase 1

Status: Withdrawn

Sponsored by: Debiopharm International SA

Summary

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

Clinical Details

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

Primary outcome:

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.

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.

Eligibility

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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.

Locations and Contacts

Additional Information

Related publications:

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.

Starting date: June 2009
Last updated: October 21, 2014

Page last updated: August 23, 2015

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